Methods and Compositions for Treating Pain Comprising a Statin

ABSTRACT

Methods and compositions are provided for reducing, treating or preventing pain and/or inflammation in a patient in need of such treatment, the methods and compositions comprising administering a therapeutically effective amount of a statin or pharmaceutically acceptable salt thereof to a target tissue site beneath the skin.

BACKGROUND

Pain can adversely affect patients in many different ways. It can keepthe patient from being active, sleeping well, enjoying family andfriends, and from eating. Pain can make the patient feel afraid ordepressed and prevent full participation in general rehabilitationprograms and may even slow recovery.

Proper pain control is of prime importance to anyone treating manydifferent diseases or conditions. Proper pain relief imparts significantphysiological and psychological benefits to the patient. Not only doeseffective pain relief mean a smoother more pleasant recovery (e.g.,mood, sleep, quality of life, etc.) with earlier discharge frommedical/surgical/outpatient facilities, but it may also reduce the onsetof chronic pain syndromes (e.g., fibromyalgia, myalgia, etc.).

Pain serves the important biological function of signaling the presenceof damage or disease within the body and is often accompanied byinflammation (redness, swelling, and/or burning). There are twocategories of pain: acute pain and neuropathic pain. Acute pain refersto pain experienced when tissue is being damaged or is damaged. Acutepain serves at least two physiologically advantageous purposes. First,it warns of dangerous environmental stimuli (such as hot or sharpobjects) by triggering reflexive responses that end contact with thedangerous stimuli. Second, if reflexive responses do not avoid dangerousenvironmental stimuli effectively, or tissue injury or infectionotherwise results, acute pain facilitates recuperative behaviors. Forexample, acute pain associated with an injury or infection encourages anorganism to protect the compromised area from further insult or usewhile the injury or infection heals. Once the dangerous environmentalstimulus is removed, or the injury or infection has resolved, acutepain, having served its physiological purpose, ends. As contrasted toacute pain, in general, neuropathic pain serves no beneficial purpose.Neuropathic pain results when pain associated with an injury orinfection continues in an area once the injury or infection hasresolved.

There are many painful disease or conditions that require proper painand/or inflammation control. Such diseases or conditions includerheumatoid arthritis, osteoarthritis, sciatica, carpal/tarsal tunnelsyndrome, lower back pain, lower extremity pain, upper extremity pain,cancer, tissue pain and pain associated with injury or repair ofcervical, thoracic, and/or lumbar vertebrae or intervertebral discs,rotator cuff, articular joint, TMJ, tendons, ligaments, muscles, or thelike.

One particularly painful disease is sciatica. Sciatica is a chronicdisease that often can be very debilitating and may take a terrible tollon those with the disease as well as their families, friends andcaregivers. Sciatica is a very painful disease associated with thesciatic nerve which runs from the lower part of the spinal cord (thelumbar region), down the back of the leg and to the foot. Sciaticagenerally begins with a herniated disc, which later leads to localimmune system activation. The herniated disc also may damage the nerveroot by pinching or compressing it, leading to additional immune systemactivation in the area.

Another particularly painful disease is spinal stenosis, where there isprogressive constriction of the spinal canal and as it narrows, thenerve elements that reside within it become progressively more crowded.Eventually, the canal dimensions become sufficiently small-so as tosignificantly compress the nerve elements and produce pain, weakness,sensory changes, clumsiness and other manifestation of nervous systemdysfunction. The disease causes lower back pain, lower extremity pain,lower extremity weakness, limitation of mobility and the high disabilityrates that often afflict the elderly.

Spondylolisthesis is another painful disease. Spondylolisthesis is adisplacement disorder of the lumbar or cervical spine, in which onevertebral body is forwardly displaced over another vertebral body.Spondylolisthesis may be caused by a traumatic event or by degenerationof the spine. At times, the displacement disorder is accompanied by orcaused by a fracture or partial collapse of one or more vertebrae ordegeneration of a disc in the spine. Patients who suffer from suchconditions can experience moderate to severe distortion of the thoracicskeletal structure, diminished ability to bear loads, loss of mobility,extreme and debilitating pain, and oftentimes suffer neurologicaldeficits in nerve function.

Statins are a family of molecules sharing the capacity to competitivelyinhibit the hepatic enzyme 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase. This enzyme catalyses the rate-limiting step in theL-mevalonate pathway for cholesterol synthesis. Oral statin use blockscholesterol synthesis and is effective in treating hypercholesterolemia.In recent years, oral statins have been shown to reducecardiovascular-related morbidity and mortality in patients with andwithout coronary disease.

To date, locally delivered statins have not been appreciated for painand/or inflammation control. New statin compositions and methods areneeded to prevent, treat or reduce pain and/or inflammation. Statincompositions and methods that reliably provide pain and/or inflammationcontrol are needed.

SUMMARY

New statin compositions and methods are provided that effectivelyprevent, treat or reduce pain and/or inflammation in chronic conditionsincluding rheumatoid arthritis, osteoarthritis, a spinal disc herniation(i.e., sciatica), carpal/tarsal tunnel syndrome, lower back pain, lowerextremity pain, upper extremity pain, cancer, tissue pain and painassociated with injury or repair of cervical, thoracic, and/or lumbarvertebrae or intervertebral discs, rotator cuff, articular joint, TMJ,tendons, ligaments, muscles, spondilothesis, stenosis, discogenic backpain, and joint pain or the like. In various embodiments, statincompositions and methods are provided that have long actinganti-inflammatory effects over periods of one day to 6 months. Invarious embodiments, new statin compositions and methods are provided,which can easily allow accurate and precise implantation of a drug depotcontaining the statin with minimal physical and psychological trauma toa patient. One advantage of the statin compositions and methods is thatthe drug depot can now be easily delivered to the target tissue site(e.g., nerve root, dorsal root ganglion, focal sites of pain, abdomen,synovial joint, at or near the spinal column, etc.) and provide painand/or inflammation relief over an extended period of time.

In one embodiment, a method is provided for treating or preventingspondylothesis, stenosis, or sciatic pain and/or inflammation in apatient in need of such treatment, the method comprising locallyadministering a therapeutically effective amount of a statin orpharmaceutically acceptable salt thereof at or near a target tissue sitebeneath the skin of the patient to treat or prevent sciatic pain and/orinflammation.

In another embodiment, a method is provided for reducing spondylothesis,stenosis, or sciatic pain and/or inflammation in a patient in need ofsuch treatment, the method comprising locally administering atherapeutically effective amount of a statin or pharmaceuticallyacceptable salt thereof at or near a target tissue site beneath the skinof the patient.

In one exemplary embodiment, an implantable drug depot is provideduseful for reducing, preventing or treating pain and/or inflammation ina patient in need of such treatment, the implantable drug depotcomprising a therapeutically effective amount of a statin orpharmaceutically acceptable salt thereof, the depot being implantable ata site beneath the skin to reduce, prevent or treat pain and/orinflammation, wherein the drug depot is capable of releasing aneffective amount of a statin or pharmaceutically acceptable salt thereofover a period of at least one day.

In another exemplary embodiment, a method of making an implantable drugdepot is provided, the method comprising combining a biocompatiblepolymer and a therapeutically effective amount of a statin orpharmaceutically acceptable salt thereof and forming the implantabledrug depot from the combination.

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In part, other aspects, features, benefits and advantages of theembodiments will be apparent with regard to the following description,appended claims and accompanying drawings where:

FIG. 1 illustrates a number of common locations within a patient wherethe parenteral statin formulation may be locally administered (e.g.,injection, infusion, depot, etc.) to the target tissue site to treatpain and/or inflammation.

FIG. 2 illustrates a schematic dorsal view of the spine and sites wherethe parenteral statin formulation may be locally administered (e.g.,injection, infusion, depot, etc.) to treat pain and/or inflammationassociated with sciatica.

FIG. 3 shows the effect of a statin (lovastatin) at different doses onpain sensitivity as measured by paw withdrawal latency to thermalradiant heat stimuli, which is a widely used nociceptive measure tostudy the hyperalgesic mechanisms.

FIG. 4 shows the effect of a statin (lovastatin) at different doses onpain sensitivity as measured by the von Frey filament test widely usedto determine tactile allodynia.

FIG. 5 shows the effect of a statin (lovastatin) at milligram,microgram, and nanogram doses on pain sensitivity as measured by pawwithdrawal latency to thermal radiant heat stimuli, which is a widelyused nociceptive measure to study the hyperalgesic mechanisms.

FIG. 6 shows the effect of a statin (lovastatin) at milligram,microgram, and nanogram doses on pain sensitivity as measured by the vonFrey filament test widely used to determine tactile allodynia.

It is to be understood that the figures are not drawn to scale. Further,the relation between objects in a figure may not be to scale, and may infact have a reverse relationship as to size. The figures are intended tobring understanding and clarity to the structure of each object shown,and thus, some features may be exaggerated in order to illustrate aspecific feature of a structure.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, reaction conditions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forth,the broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the,” include plural referents unlessexpressly and unequivocally limited to one referent. Thus, for example,reference to “a drug depot” includes one, two, three or more drugdepots.

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents, which may be included within the invention as defined bythe appended claims.

The headings below are not meant to limit the disclosure in any way;embodiments under any one heading may be used in conjunction withembodiments under any other heading.

New statin compositions and methods are provided that effectivelyprevent, treat or reduce pain and/or inflammation (e.g., acute pain,neuropathic pain, spondilothesis, stenosis, sciatica, radicular pain,etc.). In various embodiments, statin compositions and methods areprovided that have long acting anti-inflammatory effects over periods ofone day to 6 months. In various embodiments, new statin compositions andmethods are provided, which can easily allow accurate and preciseimplantation of a drug depot containing the statin with minimal physicaland psychological trauma to a patient. One advantage of the statincompositions and methods is that the drug depot can now be easilydelivered to the target tissue site (e.g., nerve root, dorsal rootganglion, focal sites of pain, abdomen, synovial joint, at or near thespinal column, etc.) and provide pain and/or inflammation relief for oneday to 6 months.

In one embodiment, a method of inhibiting, treating or preventingsciatic pain and/or inflammation in a patient is provided, the methodcomprising locally administering a therapeutically effective amount of astatin or pharmaceutically acceptable salt thereof at or near a targettissue site beneath the skin of the patient.

Statins

Statins include one or more compound(s) sharing the capacity tocompetitively inhibit the hepatic enzyme 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase. This enzyme catalyses the rate-limitingstep in the L-mevalonate pathway which is an early and rate-limitingstep in the biosynthesis of cholesterol. Consequently, statins blockcholesterol synthesis and are effective in treating hypercholesterolemiaand may reduce cardiovascular-related morbidity and mortality inpatients with and without coronary disease.

Compounds that inhibit the activity of HMG CoA reductase can be readilyidentified by using assays well known in the art; see, as examples, theassays described or cited in U.S. Pat. No. 4,231,938 at column 6, and inInternational Patent Publication WO 84/02131 at pp. 30-33.

A “therapeutically effective amount” or “effective amount” is such thatwhen administered, the drug results in alteration of the biologicalactivity, such as, for example, inhibition of inflammation, reduction oralleviation of pain, improvement in the condition, etc. It will beunderstood that the dosage administered to a patient can be as a singledose or multiple doses, continuous doses (e.g., continuous infusion) ordepot or multiple depots depending upon a variety of factors, includingthe drug's administered pharmacokinetic properties, the route ofadministration, patient conditions and characteristics (sex, age, bodyweight, health, size, etc.), extent of symptoms, concurrent treatments,frequency of treatment and the effect desired. For example, lower dailydoses of the statin may be needed when there is concurrent treatmentwith an opioid (e.g., morphine), alternatively, the patient may requirehigher doses of a statin as the dosage of the opioid (e.g., morphine) isreduced or eliminated.

In various embodiments, because the statin is locally administered,therapeutically effective doses may be less than doses used for elevatedblood/plasma cholesterol, lipids and/or triglycerides. In turn, sideeffects, such as for example, liver transaminase elevations, hepatitis,liver failure, myopathy, rhabdomyolysis and resulting renal failure,proteinuria, and/or general malaise may be reduced or eliminated.

Examples of a useful statin for treatment of pain and/or inflammationinclude, but is not limited to, atorvastatin, simvastatin, pravastatin,cerivastatin, mevastatin (see U.S. Pat. No. 3,883,140, the entiredisclosure is herein incorporated by reference), velostatin (also calledsynvinolin; see U.S. Pat. Nos. 4,448,784 and 4,450,171 these entiredisclosures are herein incorporated by reference), fluvastatin,lovastatin, rosuvastatin and fluindostatin (Sandoz XU-62-320),dalvastain (EP Appln. Publ. No. 738510 A2, the entire disclosure isherein incorporated by reference), eptastatin, pitavastatin, orpharmaceutically acceptable salts thereof or a combination thereof. Invarious embodiments, the statin may comprise mixtures of (+)R and (−)-Senantiomers of the statin. In various embodiments, the statin maycomprise a 1:1 racemic mixture of the statin.

In various embodiments, natural products such as, for example, red yeastrice; Zhitai, Cholestin or Hypocol, and Xuezhikang contain statincompounds that act as HMG CoA reductase inhibitors.

Lovastatin is a statin that may be obtained from various manufacturersin various forms (e.g., injection, powder, etc.). For example,lovastatin may be obtained from Merck as Mevacor® (see U.S. Pat. No.4,231,938, the entire disclosure is herein incorporated by reference).Suitable pharmaceutically acceptable salts of lovastatin include one ormore compounds derived from bases such as sodium hydroxide, potassiumhydroxide, lithium hydroxide, calcium hydroxide,1-deoxy-2-(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide,aluminum hydroxide, ferrous or ferric hydroxide, ammonium hydroxide ororganic amines such as N-methylglucamine, choline, arginine or the likeor combinations thereof. Suitable pharmaceutically acceptable salts ofatorvastin include lithium, calcium, hemicalcium, sodium, potassium,magnesium, aluminum, ferrous or ferric salts thereof or a combinationthereof.

In various embodiments, the therapeutically effective amount oflovastatin comprises from about 0.1 mg to about 2000 mg, for example,0.1 mg to 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg,45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg, 85 mg, 90mg, 95 mg, or 100 mg of lovastatin per day. In various embodiments,dosages of from 10 to 500 mg per day may be given, which for a normalhuman adult of approximately 70 kg is a dosage of from 0.14 to 7.1 mg/kgof body weight per day. In various embodiments, the dosage may be, forexample from 0.1 to 1.0 mg/kg per day or from about 0.3 mg/kg/day to 3mg/kg/day or from 40 ng/hr or 0.4 mcg/hr or from 6.9 mcg/kg/day to 0.68mg/kg/day.

Atorvastatin is a statin that may be obtained from various manufacturersin various forms (e.g., injection, powder, etc.). For example,atorvastatin may be obtained from Pfizer as Lipitor® (see U.S. Pat. No.5,273,995, the entire disclosure is herein incorporated by reference).The pharmaceutically acceptable salts of atorvastatin include one ormore compounds that generally can be derived by dissolving the free acidor the lactone; for example, the lactone, in aqueous or aqueous alcoholsolvent or other suitable solvents with an appropriate base andisolating the salt by evaporating the solution or by reacting the freeacid or lactone.

Suitable pharmaceutically acceptable salts of atorvastatin include oneor more compounds derived from bases, such as for example, sodiumhydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide,1-deoxy-2-(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide,aluminum hydroxide, ferrous or ferric hydroxide, ammonium hydroxide ororganic amines such as N-methylglucamine, choline, arginine or the likeor combinations thereof. Suitable pharmaceutically acceptable salts ofatorvastin include lithium, calcium, hemicalcium, magnesium, zinc,sodium, potassium, magnesium, aluminum, ferrous or ferric salts thereofor a combination thereof.

In various embodiments, the therapeutically effective amount ofatorvastatin comprises from about 0.1 mg to about 2000 mg, for example,0.1 mg to 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg,45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg, 85 mg, 90mg, 95 mg, or 100 mg of atorvastatin per day. In various embodiments,dosages of from 10 to 500 mg per day may be given, which for a normalhuman adult of approximately 70 kg is a dosage of from 0.14 to 7.1 mg/kgof body weight per day. In various embodiments, the dosage may be, forexample from 0.1 to 1.0 mg/kg per day or from about 0.3 mg/kg/day to 3mg/kg/day.

Simvastatin is a statin that may be obtained from various manufacturersin various forms (e.g., injection, powder, etc.). For example,simvastatin may be obtained from Merck as Zocor® (see U.S. Pat. No.4,444,784, the entire disclosure is herein incorporated by reference).The pharmaceutically acceptable salts of simvastatin include thoseformed from cations such as, for example, sodium, potassium, aluminum,calcium, lithium, magnesium, zinc or tetramethylammonium as well asthose salts formed from amines such as, for example, ammonia,ethylenediamine, N-methylglucamine, lysine, arginine, omithine, choline,N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine,N-benzylphenethylamine,1-p-chlorobenzyl-2-pyrrolidine-1′-yl-methylbenz-imidazole, diethylamine,piperazine, or tris(hydroxymethyl)aminomethane or a combination thereof.

In various embodiments, the therapeutically effective amount ofsimvastatin comprises from about 0.1 mg to about 2000 mg, for example,0.1 mg to 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg,45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg, 85 mg, 90mg, 95 mg, or 100 mg of simvastatin per day. In various embodiments,dosages of from 10 to 500 mg per day may be given, which for a normalhuman adult of approximately 70 kg is a dosage of from 0.14 to 7.1 mg/kgof body weight per day. In various embodiments, the dosage may be, forexample from 0.1 to 1.0 mg/kg per day or from about 0.3 mg/kg/day to 3mg/kg/day.

Pravastatin is a statin that may be obtained from various manufacturersin various forms (e.g., injection, powder, liquid, etc.). For example,pravastatin may be obtained from Bristol-Myers Squibb as Pravachol® (seeU.S. Pat. No. 4,346,227, the entire disclosure is herein incorporated byreference). Suitable pharmaceutically acceptable salts of pravastatininclude one or more compounds derived from bases or acids, such as forexample, sodium hydroxide, potassium hydroxide, lithium hydroxide,calcium hydroxide, 1-deoxy-2-(methylamino)-D-glucitol, magnesiumhydroxide, zinc hydroxide, aluminum hydroxide, ferrous or ferrichydroxide, ammonium hydroxide, hydroxy-carboxylic acids or organicamines such as N-methylglucamine, choline, arginine or the like oresters of the hydroxy-carboxylic acids of pravastatin or a combinationthereof. Suitable pharmaceutically acceptable salts of pravastatininclude lithium, calcium, hemicalcium, magnesium, zinc, sodium,potassium, magnesium, aluminum, ferrous or ferric salts thereof acombination thereof.

In various embodiments, the therapeutically effective amount ofpravastatin comprises from about 0.1 mg to about 2000 mg, for example,0.1 mg to 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg,45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg, 85 mg, 90mg, 95 mg, or 100 mg of pravastatin per day. In various embodiments,dosages of from 10 to 500 mg per day may be given, which for a normalhuman adult of approximately 70 kg is a dosage of from 0.14 to 7.1 mg/kgof body weight per day. In various embodiments, the dosage may be, forexample from 0.1 to 1.0 mg/kg per day or from about 0.3 mg/kg/day to 3mg/kg/day.

Cerivastatin (also known as rivastatin) is a statin that may be obtainedfrom various manufacturers in various forms (e.g., injection, powder,liquid, etc.). For example, cerivastatin may be obtained from Bayer AGas Baychol® (see U.S. Pat. No. 5,502,199, the entire disclosure isherein incorporated by reference). Suitable pharmaceutically acceptablesalts of cerivastatin include one or more compounds derived from bases,such as for example, sodium hydroxide, potassium hydroxide, lithiumhydroxide, calcium hydroxide, 1-deoxy-2-(methylamino)-D-glucitol,magnesium hydroxide, zinc hydroxide, aluminum hydroxide, ferrous orferric hydroxide, ammonium hydroxide or organic amines such asN-methylglucamine, choline, arginine or the like or combinationsthereof. Suitable pharmaceutically acceptable salts of cerivastatininclude lithium, calcium, hemicalcium, magnesium, zinc, sodium,potassium, magnesium, aluminum, ferrous or ferric salts thereof or acombination thereof.

In various embodiments, the therapeutically effective amount ofcerivastatin comprises from about 0.1 mg to about 2000 mg, for example,0.1 mg to 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg,45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg, 85 mg, 90mg, 95 mg, or 100 mg of cerivastatin per day. In various embodiments,dosages of from 10 to 500 mg per day may be given, which for a normalhuman adult of approximately 70 kg is a dosage of from 0.14 to 7.1 mg/kgof body weight per day. In various embodiments, the dosage may be, forexample from 0.1 to 1.0 mg/kg per day or from about 0.3 mg/kg/day to 3mg/kg/day.

Fluvastatin is a statin that may be obtained from various manufacturersin various forms (e.g., injection, powder, liquid, etc.). For example,fluvastatin may be obtained from Novartis Pharmaceuticals as Lescol®(see U.S. Pat. No. 5,354,772, the entire disclosure is hereinincorporated by reference). Some examples, of pharmaceuticallyacceptable salts include, for example, pharmaceutically acceptable saltsof phosphoric acid such as tribasic calcium phosphate or inorganiccarbonate and bicarbonate salts, e.g., sodium carbonate, sodiumbicarbonate, calcium carbonate, or mixtures thereof. Suitablepharmaceutically acceptable salts of fluvastatin include lithium,calcium, hemicalcium, magnesium, zinc, sodium, potassium, magnesium,aluminum, ferrous or ferric salts thereof or a combination thereof.

In various embodiments, the therapeutically effective amount offluvastatin comprises from about 0.1 mg to about 2000 mg, for example,0.1 mg to 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg,45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg, 85 mg, 90mg, 95 mg, or 100 mg of fluvastatin per day. For example, the dose maybe 0.1 to 10 mg/kg of body weight.

Rosuvastatin is a statin that may be obtained from various manufacturersin various forms (e.g., injection, powder, liquid, etc.). For example,rosuvastatin may be obtained from AstraZeneca as Crestor® (See U.S. Pat.Nos. 6,316,460, 6,858,618, and RE37,314, the entire disclosures areherein incorporated by reference). Suitable pharmaceutically acceptablesalts of rosuvastatin include one or more compounds derived from bases,such as for example, sodium hydroxide, potassium hydroxide, lithiumhydroxide, calcium hydroxide, 1-deoxy-2-(methylamino)-D-glucitol,magnesium hydroxide, zinc hydroxide, aluminum hydroxide, ferrous orferric hydroxide, ammonium hydroxide or organic amines such asN-methylglucamine, choline, arginine or the like or combinationsthereof. Suitable pharmaceutically acceptable salts of rosuvastatininclude lithium, calcium, hemicalcium, tribasic calcium phosphate,magnesium, zinc, sodium, potassium, magnesium, aluminum, ferrous orferric salts thereof or a combination thereof.

In various embodiments, the therapeutically effective amount ofrosuvastatin comprises from about 0.1 mg to about 2000 mg, for example,0.1 mg to 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg,45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg, 85 mg, 90mg, 95 mg, or 100 mg of rosuvastatin per day. In various embodiments,dosages of from 10 to 500 mg per day may be given, which for a normalhuman adult of approximately 70 kg is a dosage of from 0.14 to 7.1 mg/kgof body weight per day. In various embodiments, the dosage may be, forexample from 0.1 to 1.0 mg/kg per day or from about 0.3 mg/kg/day to 3mg/kg/day.

Pitavastatin is a statin that may be obtained from various manufacturersin various forms (e.g., injection, powder, liquid, etc.). Suitablepharmaceutically acceptable salts of pitavastatin include one or morecompounds derived from bases, such as for example, sodium hydroxide,potassium hydroxide, lithium hydroxide, calcium hydroxide,1-deoxy-2-(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide,aluminum hydroxide, ferrous or ferric hydroxide, ammonium hydroxide ororganic amines such as N-methylglucamine, choline, arginine or the likeor combinations thereof. Suitable pharmaceutically acceptable salts ofpitavastatin include lithium, calcium, hemicalcium, tribasic calciumphosphate, magnesium, zinc, sodium, potassium, magnesium, aluminum,ferrous or ferric salts thereof or a combination thereof.

In various embodiments, the dosage of pitavastatin can be between 1 to100 mg/day for example 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg,40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg, 85mg, 90 mg, 95 mg, or 100 mg of pitavastatin. In various embodiments,pitavastatin may be given at a dose of, for example, from 0.1 to 1.0mg/kg per day or from about 0.3 mg/kg/day to 3 mg/kg/day.

Eptastatin, velostatin, fluindostatin, or dalvastain are statins thatmay be obtained from various manufacturers in various forms (e.g.,injection, powder, liquid, etc.). Suitable pharmaceutically acceptablesalts of eptastatin, velostatin, fluindostatin, or dalvastain includeone or more compounds derived from bases, such as for example, sodiumhydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide,1-deoxy-2-(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide,aluminum hydroxide, ferrous or ferric hydroxide, ammonium hydroxide ororganic amines such as N-methylglucamine, choline, arginine or the likeor combinations thereof. Suitable pharmaceutically acceptable salts ofeptastatin, velostatin, fluindostatin, or dalvastain include lithium,calcium, hemicalcium, tribasic calcium phosphate, magnesium, zinc,sodium, potassium, magnesium, aluminum, ferrous or ferric salts thereofor a combination thereof.

In various embodiments, the dosage of eptastatin, velostatin,fluindostatin, or dalvastain can be between 1 to 100 mg/day for example5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or100 mg of eptastatin velostatin, fluindostatin, or dalvastain. Invarious embodiments, eptastatin may be given at a dose of, for example,from 0.1 to 1.0 mg/kg per day or from about 0.3 mg/kg/day to 3mg/kg/day.

The statin can be administered in parenteral formulations. The term“parenteral” as used herein refers to modes of administration, whichbypass the gastrointestinal tract, and include for example, intravenous,intramuscular, continuous or intermittent infusion, intraperitoneal,intrasternal, subcutaneous, intra-operatively, intrathecally,intradiscally, peridiscally, epidurally, perispinally, intraarticularinjection or combinations thereof.

Statin formulations for parenteral use can comprise pharmaceuticallyacceptable sterile aqueous or nonaqueous solutions, dispersions,suspensions or emulsions as well as sterile powders for reconstitutioninto sterile injectable solutions or dispersions prior to use. Examplesof suitable aqueous and nonaqueous carriers, diluents, solvents orvehicles include water, ethanol, polyols (such as glycerol, propyleneglycol, polyethylene glycol, or the like), carboxymethylcellulose orsuitable mixtures thereof or vegetable oils (such as olive oil), orinjectable organic esters such as ethyl oleate, or agents that delayabsorption (e.g., liposomes, microemulsions, etc.). In variousembodiments, the parenteral formulation may be preservative free. Invarious embodiments, the parenteral formulation may contain adjuvantssuch as preservatives (e.g., paraben, chlorobutanol, BHT, benzalkoniumchloride, etc.), wetting agents, emulsifying agents, and/or dispersingagents. The parenteral formulations may include isotonic agents such assugars, sodium chloride, or the like.

In one embodiment, one or more statins can be parenterally administeredlocally by insertion of a catheter at or near a target site (e.g., nerveroot, dorsal root ganglion, focal sites of pain, abdomen, synovialjoint, at or near the spinal column, etc.), the catheter having aproximal end and a distal end, the distal end having an opening todeliver a pharmaceutical in situ, the proximal end being fluidlyconnected, in various embodiments, to a pharmaceutical delivery pump. Invarious embodiments, a catheter or syringe is optionally operablyconnected to a pharmaceutical delivery pump. It is understood that pumpscan be internal or external as appropriate.

In various embodiments, the parenteral administration may additionallyinclude, for example, an infusion pump that administers a pharmaceuticalcomposition (e.g., statin) through a catheter near the spine or one ormore inflamed joints, an implantable mini-pump that can be inserted ator near the target site, an implantable controlled release device orsustained release delivery system that can release a certain amount ofthe statin per hour or in intermittent bolus doses. One example of asuitable pump for use is the SynchroMedo (Medtronic, Minneapolis, Minn.)pump. This pump has three sealed chambers. One contains an electronicmodule and battery. The second contains a peristaltic pump and drugreservoir. The third contains an inert gas, which provides the pressureneeded to force the pharmaceutical composition into the peristalticpump. To fill the pump, the pharmaceutical composition is injectedthrough the reservoir fill port to the expandable reservoir. The inertgas creates pressure on the reservoir, and the pressure forces thepharmaceutical composition through a filter and into the pump chamber.The pharmaceutical composition is then pumped out of the device from thepump chamber and into the catheter, which will direct it for deposit atthe target site. The rate of delivery of pharmaceutical composition iscontrolled by a microprocessor. This allows the pump to be used todeliver similar or different amounts of pharmaceutical compositioncontinuously, at specific times, or at set intervals between deliveries.

Potential drug delivery devices suitable for adaptation for the methodsdescribed herein include but are not limited to those described, forexample, in U.S. Pat. No. 6,551,290 (assigned to Medtronic, the entiredisclosure is herein incorporated by reference), which describes amedical catheter for target specific drug delivery; U.S. Pat. No.6,571,125 (assigned to Medtronic, the entire disclosure is hereinincorporated by reference), which describes an implantable medicaldevice for controllably releasing a biologically active agent; U.S. Pat.No. 6,594,880 (assigned to Medtronic, the entire disclosure is hereinincorporated by reference), which describes an intraparenchymal infusioncatheter system for delivering therapeutic agents to selected sites inan organism; and U.S. Pat. No. 5,752,930 (assigned to Medtronic, theentire disclosure is herein incorporated by reference), which describesan implantable catheter for infusing equal volumes of agents to spacedsites. In various embodiments, pumps may be adapted with apre-programmable implantable apparatus with a feedback regulateddelivery, a micro-reservoir osmotic release system for controlledrelease of chemicals, small, light-weight devices for delivering liquidmedication, implantable microminiature infusion devices, implantableceramic valve pump assemblies, or implantable infusion pumps with acollapsible fluid chamber. Alzet® osmotic pumps (Durect Corporation,Cupertino, Calif.) are also available in a variety of sizes, pumpingrates, and durations suitable for use in the described methods.

In various embodiments, the statin is locally delivered by a targeteddelivery system comprising an interbody pump and a catheter, thecatheter having a proximal end and a distal end, the distal end havingan opening to deliver a pharmaceutical composition in situ, and aproximal end of the catheter being fluidly connected to the interbodypump. It will be appreciated that a localized delivery device, such as apump or the like, may be used to deliver the statin to the targetedtissue site. Examples of localized delivery systems are presented inco-pending U.S. patent application Ser. No. 11/091,348, which isincorporated herein by reference.

In various embodiments, the statin is contained in a drug depot. A drugdepot comprises a physical structure to facilitate implantation andretention in a desired site (e.g., a synovial joint, a disc space, aspinal canal, abdominal area, a tissue of the patient, etc.). The drugdepot also comprises the drug. The term “drug” as used herein isgenerally meant to refer to any substance that alters the physiology ofa the patient. The term “drug” may be used interchangeably herein withthe terms “therapeutic agent”, “therapeutically effective amount”, and“active pharmaceutical ingredient” or “API”. It will be understood thata “drug” formulation may include more than one therapeutic agent,wherein exemplary combinations of therapeutic agents include acombination of two or more drugs. The drug depot provides aconcentration gradient of the therapeutic agent for delivery to thesite. In various embodiments, the drug depot provides an optimal drugconcentration gradient of the therapeutic agent at a distance of up toabout 0.1 cm to about 5 cm from the implant site.

In various embodiments a therapeutically effective amount of a statin isprovided to inhibit, treat and/or prevent pain or inflammation.

In addition to the statin, the drug depot may comprise one or moreadditional therapeutic agents. Examples of therapeutic agents include,those that are direct- and local-acting modulators of pro-inflammatorycytokines such as TNF-α and IL-1 including, but not limited to, solubletumor necrosis factor a receptors, any pegylated soluble tumor necrosisfactor a receptor, monoclonal or polyclonal antibodies or antibodyfragments or combinations thereof. Examples of suitable therapeuticagents include receptor antagonists, molecules that compete with thereceptor for binding to the target molecule, antisense polynucleotides,and inhibitors of transcription of the DNA encoding the target protein.Suitable examples include but are not limited to Adalimumab, Infliximab,Etanercept, Pegsunercept (PEG sTNF-R1), sTNF-R1, CDP-870, CDP-571,CNI-1493, RDP58, ISIS 104838, 1→3-β-D-glucans, Lenercept, PEG-sTNFRII FcMutein, D2E7, Afelimomab, and combinations thereof. In otherembodiments, a therapeutic agent includes metalloprotease inhibitors,glutamate antagonists, glial cell-derived neurotropic factors (GDNF), B2receptor antagonists, Substance P receptor (NK1) antagonists such ascapsaicin and civamide, downstream regulatory element antagonisticmodulator (DREAM), iNOS, inhibitors of tetrodotoxin (TTX)-resistantNa+-channel receptor subtypes PN3 and SNS2, inhibitors of interleukinssuch as IL-1, IL-6 and IL-8, and anti-inflammatory cytokines, TNFbinding protein, onercept (r-hTBP-1), recombinant adeno-associated viral(rAAV) vectors encoding inhibitors, enhancers, potentiators, orneutralizers, antibodies, including but not limited to naturallyoccurring or synthetic, double-chain, single-chain, or fragmentsthereof. For example, suitable therapeutic agents include molecules thatare based on single chain antibodies called Nanobodies™ (Ablynx, GhentBelgium), which are defined as the smallest functional fragment of anaturally occurring, single-domain antibody. Alternatively, therapeuticagents include, agents that effect kinases and/or inhibit cell signalingmitogen-activated protein kinases (MAPK), p38 MAPK, Src or proteintyrosine kinase (PTK).

Therapeutic agents include, kinase inhibitors such as, for example,Gleevec, Herceptin, Iressa, imatinib (STI571), herbimycin A, tyrphostin47, erbstatin, genistein, staurosporine, PD98059, SB203580, CNI-1493,VX-50/702 (Vertex/Kissei), SB203580, BIRB 796 (Boehringer Ingelheim),Glaxo P38 MAP Kinase inhibitor, RWJ67657 (J&J), UO126, Gd, SCIO-469(Scios), RO3201195 (Roche), Semipimod (Cytokine PharmaSciences), orderivatives thereof.

Therapeutic agents, in various embodiments, block the transcription ortranslation of TNF-a or other proteins in the inflammation cascade.Suitable therapeutic agents include, but are not limited to, integrinantagonists, alpha-4 beta-7 integrin antagonists, cell adhesioninhibitors, interferon gamma antagonists, CTLA4-Ig agonists/antagonists(BMS-188667), CD40 ligand antagonists, Humanized anti-IL-6 mAb (MRA,Tocilizumab, Chugai), HMGB-1 mAb (Critical Therapeutics Inc.), anti-IL2Rantibodies (daclizumab, basilicimab), ABX (anti IL-8 antibodies),recombinant human IL-10, or HuMax IL-15 (anti-IL 15 antibodies).

Other suitable therapeutic agents include IL-1 inhibitors, such Kineret®(anakinra) which is a recombinant, non-glycosylated form of the humaninerleukin-1 receptor antagonist (IL-1Ra), or AMG 108, which is amonoclonal antibody that blocks the action of IL-1. Therapeutic agentsalso include excitatory amino acids such as glutamate and aspartate,antagonists or inhibitors of glutamate binding to NMDA receptors, AMPAreceptors, and/or kainate receptors. Interleukin-1 receptor antagonists,thalidomide (a TNF-α release inhibitor), thalidomide analogues (whichreduce TNF-α production by macrophages), bone morphogenetic protein(BMP) type 2 and BMP-4 (inhibitors of caspase 8, a TNF-α activator),quinapril (an inhibitor of angiotensin II, which upregulates TNF-α),interferons such as IL-11 (which modulate TNF-α receptor expression),and aurin-tricarboxylic acid (which inhibits TNF-α), for example, mayalso be useful as therapeutic agents for reducing inflammation. It iscontemplated that where desirable a pegylated form of the above may beused. Examples of other therapeutic agents include NF kappa B inhibitorssuch as glucocorticoids, clonidine; antioxidants, such asdilhiocarbamate, and other compounds, such as, for example,sulfasalazine.

Specific examples of therapeutic agents suitable for use include, butare not limited to an anti-inflammatory agent, analgesic agent, orosteoinductive growth factor or a combination thereof. Anti-inflammatoryagents include, but are not limited to, salicylates, diflunisal,sulfasalazine, indomethacin, ibuprofen, naproxen, tolmetin, ketorolac,diclofenac, ketoprofen, fenamates (mefenamic acid, meclofenamic acid),enolic acids (piroxicam, meloxicam), nabumetone, celecoxib, etodolac,nimesulide, apazone, gold, sulindac or tepoxalin; antioxidants, such asdithiocarbamate, and other compounds such as sulfasalazine[2-hydroxy-5-[-4-[C2-pyridinylamino)sulfonyl]azo]benzoic acid],steroids, such as fluocinolone, cortisol, cortisone, hydrocortisone,fludrocortisone, prednisone, prednisolone, methylprednisolone,triamcinolone, betamethasone, dexamethasone, beclomethasone, fluticasoneor a combination thereof.

Suitable anabolic growth or anti-catabolic growth factors include, butare not limited to, a bone morphogenetic protein, a growthdifferentiation factor, a LIM mineralization protein, CDMP or progenitorcells or a combination thereof.

Suitable analgesic agents include, but are not limited to,acetaminophen, lidocaine, bupivacaine, ropivacaine, opioid analgesicssuch as buprenorphine, butorphanol, dextromoramide, dezocine,dextropropoxyphene, diamorphine, fentanyl, alfentanil, sufentanil,hydrocodone, hydromorphone, ketobemidone, levomethadyl, mepiridine,methadone, morphine, nalbuphine, opium, oxycodone, papaveretum,pentazocine, pethidine, phenoperidine, piritramide, dextropropoxyphene,remifentanil, tilidine, tramadol, codeine, dihydrocodeine, meptazinol,dezocine, eptazocine, flupirtine or a combination thereof.

Analgesics also include agents with analgesic properties, such as forexample, amitriptyline, carbamazepine, gabapentin, pregabalin,clonidine, or a combination thereof.

The depot may contain a muscle relaxant. Exemplary muscle relaxantsinclude by way of example and not limitation, alcuronium chloride,atracurium bescylate, baclofen, carbolonium, carisoprodol, chlorphenesincarbamate, chlorzoxazone, cyclobenzaprine, dantrolene, decamethoniumbromide, fazadinium, gallamine triethiodide, hexafluorenium,meladrazine, mephensin, metaxalone, methocarbamol, metocurine iodide,pancuronium, pridinol mesylate, styramate, suxamethonium, suxethonium,thiocolchicoside, tizanidine, tolperisone, tubocuarine, vecuronium, orcombinations thereof.

The depot comprises the therapeutic agent or agents and may also containother non-active ingredients. It has a multi-functional purposeincluding the carrying, stabilizing and controlling the release of thetherapeutic agent(s). The controlled release process, for example, maybe by a solution-diffusion mechanism or it may be governed by anerosion-controlled process. Typically, the depot will be a solid orsemi-solid formulation comprised of a biocompatible material, which canbe biodegradable. The term “solid” is intended to mean a rigid material,while, “semi-solid” is intended to mean a material that has some degreeof flexibility, thereby allowing the depot to bend and conform to thesurrounding tissue requirements.

In various embodiments, the depot material will be durable within thetissue site for a period of time equal to (for biodegradable components)or greater than (for non-biodegradable components) the planned period ofdrug delivery. For example, the depot material may have a melting pointor glass transition temperature close to or higher than bodytemperature, but lower then the decomposition or degradation temperatureof the therapeutic agent. However, the pre-determined erosion of thedepot material can also be used to provide for slow release of theloaded therapeutic agent(s).

In various embodiments, the drug depot may be designed to release thestatin when certain trigger points are reached (e.g., temperature, pH,etc.) after implantation in vivo. For example, the drug depot maycomprise polymers that will release more drug as the body temperaturereaches greater than, for example, 102° F., particularly if the drugpossesses antipyretic properties. In various embodiments, depending onthe site of implantation, the drug depot may release more or less drugas a certain pH is reached. For example, the drug depot may be designedto release the drug as the bodily fluid having a certain pH contact thedrug depot (e.g., CSF having a pH of about 7.35 to about 7.70, synovialfluid having a pH of about 7.29 to about 7.45; urine having a pH ofabout 4.6 to about 8.0, pleural fluids having a pH of about 7.2 to about7.4, blood having a pH of about 7.35 to about 7.45, etc.)

In various embodiments, the depot may have a high drug loading, suchthat the statin and/or other therapeutic agent comprises about 5-99 wt %of the depot, or 30-95 wt % of the depot, or 50-95 wt % of the depot. Invarious embodiments, the amount of a statin and/or other therapeuticagent are present in the depot in a range from about 0.1% to about 40%by weight of the depot (including 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%,6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%,21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%,35%, 36%, 37%, 38%, 39%, 40%, and ranges between any two of thesepoints, for instance, 0.1-10%, 10-20% and 20-30%, etc.). In variousembodiments, a statin can be used in a load range of 2-20%.

In various embodiments, the drug depot may release 5 mg, 10 mg, 15 mg,20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70mg, 75 mg, 75 mg, mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, or 140 mg of a statin perday for a total of 1 day to 6 months. In various embodiments, the drugdepot may release 0.1 mg to 10 mg of the statin per hour for a total of1 day to 6 months to reduce, treat or prevent pain. In variousembodiments, the drug depot releases 5%, 10%, 15%, 20%, 25%, 30%, 40%,50%, 60%, 70%, 80%, 90%, 95%, or 99% of the statin over a period of 1day to 6 months after the drug depot is administered to the targettissue site. The drug depot may have a “release rate profile” thatrefers to the percentage of active ingredient that is released overfixed units of time, e.g., mg/hr, mg/day, 10% per day for 1 day to 6months, etc. As persons of ordinary skill know a release rate profilemay be but need not be linear.

In various embodiments, the drug depot may not be biodegradable orcomprise material that is not biodegradable. Non-biodegradable polymersinclude, but are not limited to, various cellulose derivatives(carboxymethyl cellulose, cellulose acetate, cellulose acetatepropionate, ethyl cellulose, hydroxypropyl methyl cellulose,hydroxyalkyl methyl celluloses, and alkyl celluloses), silicon andsilicon-based polymers (such as polydimethylsiloxane),polyethylene-co-(vinyl acetate), poloxamer, polyvinylpyrrolidone,poloxamine, polypropylene, polyamide, polyacetal, polyester, polyethylene-chlorotrifluoroethylene, polytetrafluoroethylene (PTFE or“Teflon™”), styrene butadiene rubber, polyethylene, polypropylene,polyphenylene oxide-polystyrene, poly-α-chloro-p-xylene,polymethylpentene, polysulfone, non-degradable ethylene-vinyl acetate(e.g., ethylene vinyl acetate disks and poly(ethylene-co-vinylacetate)), and other related biostable polymers or combinations thereof.Exemplary non-biodegradable material include, for example, polyurethane,polyurea, polyether(amide), PEBA, thermoplastic elastomeric olefin,copolyester, and styrenic thermoplastic elastomer, steel, aluminum,stainless steel, titanium, metal alloys with high non-ferrous metalcontent and a low relative proportion of iron, carbon fiber, glassfiber, plastics, ceramics or combinations thereof.

The drug depot may comprise non-resorbable polymers as well. Thesenon-resorbable polymers can include, but are not limited to, delrin,polyurethane, copolymers of silicone and polyurethane, polyolefins (suchas polyisobutylene and polyisoprene), acrylamides (such as polyacrylicacid and poly(acrylonitrile-acrylic acid)), neoprene, nitrile, acrylates(such as polyacrylates, poly(2-hydroxy ethyl methacrylate), methylmethacrylate, 2-hydroxyethyl methacrylate, and copolymers of acrylateswith N-vinyl pyrrolidone), N-vinyl lactams, polyacrylonitrile,glucomannan gel, vulcanized rubber and combinations thereof. Examples ofpolyurethanes include thermoplastic polyurethanes, aliphaticpolyurethanes, segmented polyurethanes, hydrophilic polyurethanes,polyether-urethane, polycarbonate-urethane and siliconepolyether-urethane. Typically, the non-degradable drug depots may needto be removed. Typically, these types of drug depots may need to beremoved.

In some instances, it may be desirable to avoid having to remove thedrug depot after use. In those instances, the depot may comprise abiodegradable material. There are numerous materials available for thispurpose and having the characteristic of being able to breakdown ordisintegrate over a prolonged period of time when positioned at or nearthe target tissue. As a function of the chemistry of the biodegradablematerial the mechanism of the degradation process can be hydrolytical orenzymatical in nature, or both. In various embodiments, the degradationcan occur either at the surface (heterogeneous or surface erosion) oruniformly throughout the drug delivery system depot (homogeneous or bulkerosion).

A “depot” includes but is not limited to capsules, microspheres,microparticles, microcapsules, microfibers particles, nanospheres,nanoparticles, coating, matrices, wafers, pills, pellets, emulsions,liposomes, micelles, gels, or other pharmaceutical deliverycompositions. Suitable materials for the depot are ideallypharmaceutically acceptable biodegradable and/or any bioabsorbablematerials that are preferably FDA approved or GRAS materials. Thesematerials can be polymeric or non-polymeric, as well as synthetic ornaturally occurring, or a combination thereof. The depot may alsocomprise a drug pump.

The term “biodegradable” includes that all or parts of the drug depotwill degrade over time by the action of enzymes, by hydrolytic actionand/or by other similar mechanisms in the human body. In variousembodiments, “biodegradable” includes that depot (e.g., microparticle,microsphere, gel, etc.) can break down or degrade within the body tonon-toxic components after or while a therapeutic agent has been or isbeing released. By “bioerodible” it is meant that the depot and/or gelwill erode or degrade over time due, at least in part, to contact withsubstances found in the surrounding tissue, fluids or by cellularaction. By “bioabsorbable” it is meant that the depot will be brokendown and absorbed within the human body, for example, by a cell ortissue. “Biocompatible” means that the depot will not cause substantialtissue irritation or necrosis at the target tissue site.

In various embodiments, the depot may comprise a biocompatible,bioabsorbable, and/or a biodegradable biopolymer that may provideimmediate release, sustained release or controlled release of the drug.Examples of suitable sustained release biopolymers include but are notlimited to poly (alpha-hydroxy acids), poly (lactide-co-glycolide)(PLGA), polylactide (PLA), polyglycolide (PG), polyethylene glycol(PEG), PEG 200, PEG 300, PEG 400, PEG 500, PEG 550, PEG 600, PEG 700,PEG 800, PEG 900, PEG 1000, PEG 1450, PEG 3350, PEG 4500, PEG 8000,conjugates of poly (alpha-hydroxy acids), polyorthoesters, polyaspirins,polyphosphagenes, collagen, starch, pre-gelatinized starch, hyaluronicacid, chitosans, gelatin, alginates, albumin, fibrin, vitamin E analogs,such as alpha tocopheryl acetate, d-alpha tocopheryl succinate,D,L-lactide, or L-lactide, ,-caprolactone, dextrans, vinylpyrrolidone,polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (polyactive),methacrylates, poly (N-isopropylacrylamide), PEO-PPO-PEO (pluronics),PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407,PEG-PLGA-PEG triblock copolymers, SAIB (sucrose acetate isobutyrate)hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylmethylcellulose, carboxymethylcellulose or salts thereof, Carbopol,poly(hydroxyethylmethacrylate), poly(methoxyethylmethacrylate),poly(methoxyethoxy-ethylmethacrylate), polymethylmethacrylate (PMMA),methylmethacrylate (MMA), gelatin, polyvinyl alcohols, propylene glycol,or combinations thereof.

In various embodiments, when the drug depot comprises a polymer, it isemployed at about 10 wt % to about 99 wt % or about 30 wt % to about 60wt % based on the weight of the drug depot.

In various embodiments, the drug depot comprisespoly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide(PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-ε-caprolactone,D,L-lactide-glycolide-ε-caprolactone, glycolide-caprolactone or acombination thereof.

The depot may optionally contain inactive materials such as bufferingagents and pH adjusting agents such as potassium bicarbonate, potassiumcarbonate, potassium hydroxide, sodium acetate, sodium borate, sodiumbicarbonate, sodium carbonate, sodium hydroxide or sodium phosphate;degradation/release modifiers; drug release adjusting agents;emulsifiers; preservatives such as benzalkonium chloride, chlorobutanol,phenylmercuric acetate and phenylmercuric nitrate, sodium bisulfite,sodium bisulfate, sodium thiosulfate, thimerosal, methylparaben,polyvinyl alcohol and phenylethyl alcohol; solubility adjusting agents;stabilizers; and/or cohesion modifiers. Typically, any such inactivematerials will be present within the range of 0-75 wt %, and moretypically within the range of 0-30 wt %. If the depot is to be placed inthe spinal area or joint area, in various embodiments, the depot maycomprise sterile preservative free material.

The depot can be different sizes, shapes and configurations. There areseveral factors that can be taken into consideration in determining thesize, shape and configuration of the drug depot. For example, both thesize and shape may allow for ease in positioning the drug depot at thetarget tissue site that is selected as the implantation or injectionsite. In addition, the shape and size of the system should be selectedso as to minimize or prevent the drug depot from moving afterimplantation or injection. In various embodiments, the drug depot can beshaped like a sphere, a cylinder such as a rod or fiber, a flat surfacesuch as a disc, film, ribbon or sheet, or the like. Flexibility may be aconsideration so as to facilitate placement of the drug depot. Invarious embodiments, the drug depot can be different sizes, for example,the drug depot may be a length of from about 0.01 mm to 5 mm and have adiameter of from about 0.01 to about 2 mm. In various embodiments, thedrug depot may have a layer thickness of from about 0.005 to 1.0 mm,such as, for example, from 0.05 to 0.75 mm.

Radiographic markers can be included on the drug depot to permit theuser to accurately position the depot into the target site of thepatient. These radiographic markers will also permit the user to trackmovement and degradation of the depot at the site over time. In thisembodiment, the user may accurately position the depot in the site usingany of the numerous diagnostic imaging procedures. Such diagnosticimaging procedures include, for example, X-ray imaging or fluoroscopy.Examples of such radiographic markers include, but are not limited to,barium, calcium, and/or metal beads or particles. Where present, theradiographic marker is typically present in an amount of from about 10%to about 40% (including 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%,19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%,33%, 34%, 35%, 36%, 37%, 38%, 39% and 40%, as well as ranges between anytwo of these values, e.g., 10-15%, 15-20%, 20-25%, 25-30%, 30-35%,35-40%, and so forth, with 15-30% being more typical, even moretypically 20-25%). In various embodiments, the radiographic marker couldbe a spherical shape or a ring around the depot.

In one exemplary embodiment, a drug depot for delivering a therapeuticagent to a target tissue site beneath the skin of a patient is provided,the drug depot comprising an effective amount of a statin, wherein thetarget tissue site comprises at least one muscle, ligament, tendon,cartilage, spinal disc, spinal foraminal space near the spinal nerveroot, facet or synovial joint, or spinal canal.

In various embodiments, the drug depot comprises a gel, which includes asubstance having a gelatinous, jelly-like, or colloidal properties atroom temperature. The gel, in various embodiments, may have the statinand optionally one or more additional therapeutic agents dispersedthroughout it or suspended within the gel. The dispersal of thetherapeutic agent may be even throughout the gel. Alternatively, theconcentration of the therapeutic agent may vary throughout it. As thebiodegradable material of the gel or drug depot degrades at the site,the therapeutic agent is released.

When the drug depot is a gel, in contrast to a sprayable gel thattypically employs a low viscosity polymer, a gel with a higher viscositymay be desirable for other applications, for example, a gel having aputty-like consistency may be more preferable for bone regenerationapplications.

In another exemplary embodiment, a viscous gel is provided that isloaded with one or more drug depots (e.g., microspheres loaded with atherapeutic agent), wherein the viscous gel is positioned into asynovial joint, disc space, a spinal canal, or a soft tissue surroundingthe spinal canal of a subject. The gel can also be used, in variousembodiments, to seal or repair tissue. In yet another exemplaryembodiment, the gel is injectable, and/or an adherent gel thatsolidifies upon contact with tissue. For example, the gel may beadministered as a liquid that gels in situ at the target tissue site. Invarious embodiments, the gel can comprise a two part system where aliquid is administered and a gelling agent is added subsequently tocause the liquid to gel or harden.

In various embodiments, the drug depot is loaded with a statin andoptionally one or more additional therapeutic agents, and delivered tothe desired target tissue site (e.g., surgical wound site, inflammedtissue, degenerative tissue, etc.) and, in various embodiments, the drugdepot may be held in place by a suture, barb, staple, adhesive gel, etc.which prevents the drug depot from being removed from that site by thevenous systemic circulation or otherwise dispersed too widely, whichreduces the desired therapeutic effect. For example, after hours ordays, the drug depot may degrade, thereby allowing the drug depots(e.g., microspheres) to begin releasing the therapeutic agent. Themicrospheres do not begin releasing the agent until they are releasedfrom the drug depot. So, the microspheres may be formed from aninsoluble or inert substances, but soluble or active once it comes intocontact with the target tissue site. Likewise, the drug depot maycomprise a substance that dissolves or disperses within the tissue. Asthe drug depot begins to dissolve within hours to days, the drug depots(e.g., microspheres) are exposed to body fluids and begin releasingtheir contents. The drug depot can be formulated to optimize exposuretime of the drug depot and release of the therapeutic agent from thedrug depot. In various embodiments, the drug depot (e.g., gel) isflowable and can be injected, sprayed, instilled, and/or dispensed to,on or in the target tissue site. “Flowable” means that the gelformulation is easy to manipulate and may be brushed, sprayed, dripped,injected, shaped and/or molded at or near the target tissue site as itcoagulates. “Flowable” includes formulations with a low viscosity orwater-like consistency to those with a high viscosity, such as apaste-like material. In various embodiments, the flowability of theformulation allows it to conform to irregularities, crevices, cracks,and/or voids in the tissue site. For example, in various embodiments,the gel may be used to fill one or more voids in an osteolytic lesion.

In various embodiments, the drug depot comprises poly (alpha-hydroxyacids), poly (lactide-co-glycolide) (PLGA), polylactide (PLA),polyglycolide (PG), polyethylene glycol (PEG) conjugates of poly(alpha-hydroxy acids), polyorthoesters, polyaspirins, polyphosphagenes,collagen, starch, pre-gelatinized starch, hyaluronic acid, chitosans,gelatin, alginates, albumin, fibrin, vitamin E analogs, such as alphatocopheryl acetate, d-alpha tocopheryl succinate, D,L-lactide, orL-lactide, ,-caprolactone, dextrans, vinylpyrrolidone, polyvinyl alcohol(PVA), PVA-g-PLGA, PEGT-PBT copolymer (polyactive), methacrylates, poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics), PEO-PPO-PAAcopolymers, PLGA-PEO-PLGA, PEG-PLG (poly(d,l-lactide-co-glycolide),PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB (sucroseacetate isobutyrate) or combinations thereof. These one or morecomponents allow the therapeutic agent to be released from the drugdepot in a controlled and/or sustained manner. For example, the drugdepot containing the therapeutic agent and a polymer matrix can beinjected at the target tissue site and the polymer matrix breaks downover time (e.g., hours, days) within the target tissue site releasing astatin and optionally additional therapeutic agents. Thus theadministration of the drug depot can be localized and occur over aperiod of time (e.g., at least one day to about 2, 3, 4, 5, 6, 7, 8, 9,10 days or months). In some embodiments, the therapeutically effectivedosage amount (e.g., statin) and the release rate profile are sufficientto reduce inflammation and/or pain for a period of at least one day, forexample, 1-90 days, 1-10 days, 1-3 days, 3-7 days, 3-12 days; 3-14 days,7-10 days, 7-14 days, 7-21 days, 7-30 days, 7-50 days, 7-90 days, 7-140days, 14-140 days, 3 days to 150 days, or 3 days to 6 months or 1 year.

The terms “sustained release” (e.g., extended release or controlledrelease) are used herein to refer to one or more therapeutic agent(s)that is introduced into the body of a human or other mammal andcontinuously releases a stream of one or more therapeutic agents over apredetermined time period and at a therapeutic level sufficient toachieve a desired therapeutic effect throughout the predetermined timeperiod. Reference to a continuous release stream is intended toencompass release that occurs as the result of biodegradation in vivo ofthe drug depot, or a matrix or component thereof, or as the result ofmetabolic transformation or dissolution of the therapeutic agent(s) orconjugates of therapeutic agent(s).

In various embodiments, the drug depot can be designed to cause aninitial burst dose of therapeutic agent within the first 24 hours afterimplantation. “Initial burst” or “burst effect” or “bolus dose” refersto the release of therapeutic agent from the drug depot during the first24 hours after the drug depot comes in contact with an aqueous fluid(e.g., synovial fluid, cerebral spinal fluid, etc.). In variousembodiments, the drug depot is designed to avoid this initial bursteffect.

In various embodiments, the drug depot contains one or more differentrelease layer(s) that releases a bolus dose of a statin orpharmaceutically acceptable salt thereof (e.g., 5 mg to 60 mg at atarget site beneath the skin) and one or more sustain release layer(s)that releases an effective amount of a statin or pharmaceuticallyacceptable salt thereof over a period of one day to 6 months. In variousembodiments, the one or more immediate release layer(s) comprise PLGA,which degrades faster and than the one or more sustain release layer(s),which comprises PLA, which degrades at a slower rate than the PLGA.

In various embodiments, when the drug depot comprises a gel, the gel mayhave a pre-dosed viscosity in the range of about 1 to about 500centipoise (cps), 1 to about 200 cps, or 1 to about 100 cps. After thegel is administered to the target site, the viscosity of the gel willincrease and the gel will have a modulus of elasticity (Young's modulus)in the range of about 1×10⁴ to about 6×10⁵ dynes/cm², or 2×10⁴ to about5×10⁵ dynes/cm², or 5×10⁴ to about 5×10⁵ dynes/cm².

In one embodiment, the gel may be an adherent gel, which comprises atherapeutic agent that is evenly distributed throughout the gel. The gelmay be of any suitable type, as previously indicated, and should besufficiently viscous so as to prevent the gel from migrating from thetargeted delivery site once deployed; the gel should, in effect, “stick”or adhere to the targeted tissue site. The gel may, for example,solidify upon contact with the targeted tissue or after deployment froma targeted delivery system. The targeted delivery system may be, forexample, a syringe, a catheter, needle or cannula or any other suitabledevice. The targeted delivery system may inject or spray the gel into oron the targeted tissue site. The therapeutic agent may be mixed into thegel prior to the gel being deployed at the targeted tissue site. Invarious embodiments, the gel may be part of a two-component deliverysystem and when the two components are mixed, a chemical process isactivated to form the gel and cause it to stick or adhere to the targettissue.

In various embodiments, for those gel formulations that contain apolymer, the polymer concentration may affect the rate at which the gelhardens (e.g., a gel with a higher concentration of polymer maycoagulate more quickly than gels having a lower concentration ofpolymer). In various embodiments, when the gel hardens, the resultingmatrix is solid but is also able to conform to the irregular surface ofthe tissue (e.g., recesses and/or projections in bone).

The percentage of polymer present in the gel may also affect theviscosity of the polymeric composition. For example, a compositionhaving a higher percentage by weight of polymer is typically thicker andmore viscous than a composition having a lower percentage by weight ofpolymer. A more viscous composition tends to flow more slowly.Therefore, a composition having a lower viscosity may be preferred insome instances, for example when applying the formulation via spray.

In various embodiments, the molecular weight of the gel can be varied bymany methods known in the art. The choice of method to vary molecularweight is typically determined by the composition of the gel (e.g.,polymer, versus non-polymer). For example in various embodiments, whenthe gel comprises one or more polymers, the degree of polymerization canbe controlled by varying the amount of polymer initiators (e.g. benzoylperoxide), organic solvents or activator (e.g. DMPT), crosslinkingagents, polymerization agent, and/or reaction time.

Suitable gel polymers may be soluble in an organic solvent. Thesolubility of a polymer in a solvent varies depending on thecrystallinity, hydrophobicity, hydrogen-bonding and molecular weight ofthe polymer. Lower molecular weight polymers will normally dissolve morereadily in an organic solvent than high-molecular weight polymers. Apolymeric gel, which includes a high molecular weight polymer, tends tocoagulate or solidify more quickly than a polymeric composition, whichincludes a low-molecular weight polymer. Polymeric gel formulations,which include high molecular weight polymers, also tend to have a highersolution viscosity than a polymeric gel, which include a low-molecularweight polymer.

In various embodiments, the gel can have a viscosity of about 300 toabout 5,000 centipoise (cp). In other embodiments, the gel can have aviscosity of from about 5 to about 300 cps, from about 10 cps to about50 cps, from about 15 cps to about 75 cps at room temperature, whichallows it to be sprayed at or near the target site.

In various embodiments, the drug depot may comprise material to enhanceviscosity and control the release of the drug such material may include,for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose,hydroxyethyl methylcellulose, carboxymethylcellulose and salts thereof,Carbopol, poly(hydroxyethylmethacrylate),poly(methoxyethylmethacrylate),poly(methoxyethoxy-ethylmethacrylate),polymethyl-methacrylate (PMMA), methylmethacrylate (MMA), gelatin,polyvinyl alcohols, propylene glycol, PEG 200, PEG 300, PEG 400, PEG500, PEG 550, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1450,PEG 3350, PEG 4500, PEG 8000 or combinations thereof. For example, invarious embodiments, the drug depot comprises from about 2.5% to 60% byweight of a statin, which is sprayed with from about 40% to 60% byweight PLGA, 5% to 40% by weight of PEG550.

In various embodiments, the molecular weight of the polymer can be awide range of values. The average molecular weight of the polymer can befrom about 1000 to about 10,000,000; or about 1,000 to about 1,000,000;or about 5,000 to about 500,000; or about 10,000 to about 100,000; orabout 20,000 to 50,000.

When there are other active ingredients, surfactants, excipients orother ingredients or combinations thereof in the formulation, in someembodiments, these other compounds or combinations thereof comprise lessthan 20 wt. %, less than 19 wt. %, less than 18 wt. %, less than 17 wt.%, less than 16 wt. %, less than 15 wt. %, less than 14 wt. %, less than13 wt. %, less than 12 wt. %, less than 11 wt. %, less than 10 wt. %,less than 9 wt. %, less than 8 wt. %, less than 7 wt. %, less than 6 wt.%, less than 5 wt. %, less than 4 wt. %, less than 3 wt. %, less than 2wt. %, less than 1 wt. % or less than 0.5 wt. %. Exemplary excipientsinclude but are not limited to mPEG, D-Sorbital, maltodextran,cyclodextrin and combinations thereof.

The drug depot release profile can also be controlled, among otherthings, by controlling the particle size distribution of the componentsof the drug depot. In various embodiments, the particle sizedistribution of the components of the drug depot (e.g., statin, gel,etc.) may be in the range of from about 10 μM to 100 μM so that the drugdepot can easily be delivered to or at or near the target site byinjection, spraying, instilling, etc.

In some embodiments, at least 75% of the particles have a size fromabout 1 micrometer to about 250 micrometers. In some embodiments, atleast 85% of the particles have a size from about 5 micrometer to about100 micrometers. In some embodiments, at least 95% of the particles havea size from about 10 micrometer to about 30 micrometers. In someembodiments, all of the particles have a size from about 10 micrometerto about 250 micrometers.

As persons of ordinary skill in the art are aware, implantable depotcompositions having a blend of polymers with different end groups areused the resulting formulation will be able to regulate the duration ofdelivery. For example, one may use polymers with acid (e.g., carboxylicacid) and ester end groups (e.g., methyl of ethyl ester end groups).

Additionally, by varying the comonomer ratio of the various monomersthat form a polymer (e.g., the L/G (lactic acid/glycolic acid) or G/CL(glycolic acid/polycaprolactone) ratio for a given polymer) there willbe a resulting depot composition having a regulated burst index andduration of delivery. For example, a depot composition having a polymerwith a L/G ratio of 50:50 may have a short duration of delivery rangingfrom about two days to about one month; a depot composition having apolymer with a L/G ratio of 65:35 may have a duration of delivery ofabout two months; a depot composition having a polymer with a L/G ratioof 75:25 or L/CL ratio of 75:25 may have a duration of delivery of aboutthree months to about four months; a depot composition having a polymerratio with a L/G ratio of 85:15 may have a duration of delivery of aboutfive months; a depot composition having a polymer with a L/CL ratio of25:75 or PLA may have a duration of delivery greater than or equal tosix months; a depot composition having a terpolymer of CL/G/L with Ggreater than 50% and L greater than 10% may have a duration of deliveryof about one month and a depot composition having a terpolymer of CL/G/Lwith G less than 50% and L less than 10% may have a duration months upto six months. In general, increasing the G content relative to the CLcontent shortens the duration of delivery whereas increasing the CLcontent relative to the G content lengthens the duration of delivery.Thus, among other things, depot compositions having a blend of polymershaving different molecular weights, end groups and comonomer ratios canbe used to create a depot formulation having a lower burst index and aregulated duration of delivery.

In various embodiments, the drug depot may comprise a hydrogel made ofhigh molecular weight biocompatible elastomeric polymers of synthetic ornatural origin. A desirable property for the hydrogel to have is theability to respond rapidly to mechanical stresses, particularly shearsand loads, in the human body.

Hydrogels obtained from natural sources are particularly appealing sincethey are more likely to be biodegradable and biocompatible for in vivoapplications. Suitable hydrogels include natural hydrogels, such as forexample, gelatin, collagen, silk, elastin, fibrin andpolysaccharide-derived polymers like agarose, and chitosan, glucomannangel, hyaluronic acid, polysaccharides, such as cross-linkedcarboxyl-containing polysaccharides, or a combination thereof. Synthetichydrogels include, but are not limited to those formed from polyvinylalcohol, acrylamides such as polyacrylic acid and poly(acrylonitrile-acrylic acid), polyurethanes, polyethylene glycol (e.g.,PEG 3350, PEG 4500, PEG 8000), silicone, polyolefins such aspolyisobutylene and polyisoprene, copolymers of silicone andpolyurethane, neoprene, nitrile, vulcanized rubber,poly(N-vinyl-2-pyrrolidone), acrylates such as poly(2-hydroxy ethylmethacrylate) and copolymers of acrylates with N-vinyl pyrolidone,N-vinyl lactams, polyacrylonitrile or combinations thereof. The hydrogelmaterials may further be cross-linked to provide further strength asneeded. Examples of different types of polyurethanes includethermoplastic or thermoset polyurethanes, aliphatic or aromaticpolyurethanes, polyetherurethane, polycarbonate-urethane or siliconepolyether-urethane, or a combination thereof.

In various embodiments, rather than directly admixing the therapeuticagent into the drug depot, microspheres may be dispersed within the drugdepot, the microspheres loaded with the therapeutic agent. In oneembodiment, the microspheres provide for a sustained release of thetherapeutic agent. In yet another embodiment, the drug depot, which isbiodegradable, prevents the microspheres from releasing the therapeuticagent; the microspheres thus do not release the therapeutic agent untilthey have been released from the depot. For example, a drug depot may bedeployed around a target tissue site (e.g., DRG, synovial joint, etc.).Dispersed within the drug depot are a plurality of microspheres thatencapsulate the desired therapeutic agent. Certain of these microspheresdegrade once released from the drug depot, thus releasing thetherapeutic agent.

Microspheres, much like a fluid, may disperse relatively quickly,depending upon the surrounding tissue type, and hence disperse thetherapeutic agent. In some situations, this may be desirable; in others,it may be more desirable to keep the therapeutic agent tightlyconstrained to a well-defined target site.

Cannula or Needle

It will be appreciated by those with skill in the art that the depot canbe administered to the target site using a cannula or needle that can bea part of a drug delivery device e.g., a syringe, a gun drug deliverydevice, or any medical device suitable for the application of a drug toa targeted organ or anatomic region. The cannula or needle of the drugdepot device is designed to cause minimal physical and psychologicaltrauma to the patient.

Cannulas or needles include tubes that may be made from materials, suchas for example, polyurethane, polyurea, polyether(amide), PEBA,thermoplastic elastomeric olefin, copolyester, and styrenicthermoplastic elastomer, steel, aluminum, stainless steel, titanium,metal alloys with high non-ferrous metal content and a low relativeproportion of iron, carbon fiber, glass fiber, plastics, ceramics orcombinations thereof. The cannula or needle may optionally include oneor more tapered regions. In various embodiments, the cannula or needlemay be beveled. The cannula or needle may also have a tip style vitalfor accurate treatment of the patient depending on the site forimplantation. Examples of tip styles include, for example, Trephine,Coumand, Veress, Huber, Seldinger, Chiba, Francine, Bias, Crawford,deflected tips, Hustead, Lancet, or Tuohey. In various embodiments, thecannula or needle may also be non-coring and have a sheath covering itto avoid unwanted needle sticks.

The dimensions of the hollow cannula or needle, among other things, willdepend on the site for implantation. For example, the width of theepidural space is only about 3-5 mm for the thoracic region and about5-7 mm for the lumbar region. Thus, the needle or cannula, in variousembodiments, can be designed for these specific areas. In variousembodiments, the cannula or needle may be inserted using atransforaminal approach in the spinal foramen space, for example, alongan inflammed nerve root and the drug depot implanted at this site fortreating the condition. Typically, the transforaminal approach involvesapproaching the intervertebral space through the intervertebralforamina.

Some examples of lengths of the cannula or needle may include, but arenot limited to, from about 50 to 150 mm in length, for example, about 65mm for epidural pediatric use, about 85 mm for a standard adult andabout 110 mm for an obese adult patient. The thickness of the cannula orneedle will also depend on the site of implantation. In variousembodiments, the thickness includes, but is not limited to, from about0.05 to about 1.655. The gauge of the cannula or needle may be thewidest or smallest diameter or a diameter in between for insertion intoa human or animal body. The widest diameter is typically about 14 gauge,while the smallest diameter is about 22 gauge. In various embodimentsthe gauge of the needle or cannula is about 18 to about 22 gauge.

In various embodiments, like the drug depot, the cannula or needleincludes dose radiographic markers that indicate location at or near thesite beneath the skin, so that the user may accurately position thedepot at or near the site using any of the numerous diagnostic imagingprocedures. Such diagnostic imaging procedures include, for example,X-ray imaging or fluoroscopy. Examples of such radiographic markersinclude, but are not limited to, barium, calcium, and/or metal beads orparticles.

In various embodiments, the needle or cannula may include a transparentor translucent portion that can be visualizable by ultrasound,fluoroscopy, x-ray, or other imaging techniques. In such embodiments,the transparent or translucent portion may include a radiopaque materialor ultrasound responsive topography that increases the contrast of theneedle or cannula relative to the absence of the material or topography.

The drug depot, pharmaceutical formulation, and/or medical device toadminister the drug may be sterilizable. In various embodiments, one ormore components of the drug depot, pharmaceutical formulation, and/ormedical device to administer the drug are sterilized by radiation in aterminal sterilization step in the final packaging. Terminalsterilization of a product provides greater assurance of sterility thanfrom processes such as an aseptic process, which require individualproduct components to be sterilized separately and the final packageassembled in a sterile environment.

Typically, in various embodiments, gamma radiation is used in theterminal sterilization step, which involves utilizing ionizing energyfrom gamma rays that penetrates deeply in the device. Gamma rays arehighly effective in killing microorganisms, they leave no residues norhave sufficient energy to impart radioactivity to the device. Gamma rayscan be employed when the device is in the package and gammasterilization does not require high pressures or vacuum conditions,thus, package seals and other components are not stressed. In addition,gamma radiation eliminates the need for permeable packaging materials.

In various embodiments, electron beam (e-beam) radiation may be used tosterilize one or more components of the device. E-beam radiationcomprises a form of ionizing energy, which is generally characterized bylow penetration and high-dose rates. E-beam irradiation is similar togamma processing in that it alters various chemical and molecular bondson contact, including the reproductive cells of microorganisms. Beamsproduced for e-beam sterilization are concentrated, highly-chargedstreams of electrons generated by the acceleration and conversion ofelectricity. E-beam sterilization may be used, for example, when thedrug depot is included in a gel.

Other methods may also be used to sterilize the depot, pharmaceuticalformulation, and/or one or more components of the device, including, butnot limited to, gas sterilization, such as, for example, with ethyleneoxide or steam sterilization.

In various embodiments, a kit is provided that may include additionalparts along with the drug depot, pharmaceutical formulation, and/ormedical device combined together to be used to implant the drug depot(e.g., ribbon-like fibers). The kit may include the drug depot device ina first compartment. The second compartment may include a canisterholding the drug depot or pharmaceutical formulation and any otherinstruments needed for the localized drug delivery. A third compartmentmay include gloves, drapes, wound dressings and other proceduralsupplies for maintaining sterility of the implanting process, as well asan instruction booklet. A fourth compartment may include additionalcannulas and/or needles. Each tool may be separately packaged in aplastic pouch that is radiation sterilized. A cover of the kit mayinclude illustrations of the implanting procedure and a clear plasticcover may be placed over the compartments to maintain sterility.

Drug Delivery

In various embodiments, a method for delivering a statin into a targettissue site of a patient is provided, the method comprising inserting acannula at or near a target tissue site and implanting the drug depotcontaining the statin at the target site beneath the skin of thepatient. In various embodiments, to administer the drug depot to thedesired site, first the cannula or needle can be inserted through theskin and soft tissue down to the target tissue site and the drug depotadministered (e.g., injected, implanted, instilled, sprayed, etc.) at ornear the target site. In those embodiments where the drug depot isseparate from the gel, first the cannula or needle can be insertedthrough the skin and soft tissue down to the site of injection and oneor more base layer(s) of gel can be administered to the target site.Following administration of the one or more base layer(s), the drugdepot can be implanted on or in the base layer(s) so that the gel canhold the depot in place or reduce migration. If required a subsequentlayer or layers of gel can be applied on the drug depot to surround thedepot and further hold it in place. Alternatively, the drug depot may beimplanted first and then the gel placed (e.g., brushed, dripped,injected, or painted, etc.) around the drug depot to hold it in place.By using the gel, accurate and precise implantation of a drug depot canbe accomplished with minimal physical and psychological trauma to thepatient. In various embodiments, the drug depot can be sutured to thetarget site or alternatively the drug depot can be implanted, withoutsuturing. For example, in various embodiments, the drug depot can be aribbon shaped depot and placed at the target site, before, during orafter surgery.

In various embodiments, when the target tissue site comprises a spinalregion, a portion of fluid (e.g., spinal fluid, etc.) can be withdrawnfrom the target site through the cannula or needle first and then thedepot administered (e.g., placed, dripped, injected, or implanted,etc.). The target site will re-hydrate (e.g., replenishment of fluid)and this aqueous environment will cause the drug to be released from thedepot.

Treating or treatment of a disease or condition refers to executing aprotocol, which may include administering one or more drugs to a patient(human, other normal or otherwise), in an effort to alleviate signs orsymptoms of the disease. Alleviation can occur prior to signs orsymptoms of the disease or condition appearing, as well as after theirappearance. Thus, “treating” or “treatment” may include “preventing” or“prevention” of disease or undesirable condition. In addition,“treating” or “treatment” does not require complete alleviation of signsor symptoms, does not require a cure, and specifically includesprotocols that have only a marginal effect on the patient. “Reducingpain” includes a decrease in pain and does not require completealleviation of pain signs or symptoms, and does not require a cure. Invarious embodiments, reducing pain includes even a marginal decrease inpain. By way of example, the administration of one or more effectivedosages of the statin may be used to prevent, treat or relieve thesymptoms of post-operative pain and/or inflammation incidental tosurgery.

“Localized” delivery includes, delivery where one or more drugs aredeposited within, at or near a tissue. For example, localized deliveryincludes delivery to a nerve root of the nervous system or a region ofthe brain, or in close proximity (within about 10 cm, or preferablywithin about 5 cm, for example) thereto. “Targeted delivery system”provides delivery of one or more drugs depots (e.g., gels or depotdispersed in the gel, etc.) having a quantity of therapeutic agent thatcan be deposited at or near the target tissue site as needed fortreatment of pain and/or inflammation incidental to surgery.

FIG. 1 illustrates a number of common locations within a patient thatmay be subject to pain. It will be recognized that the locationsillustrated in FIG. 1 are merely exemplary of the many differentlocations within a patient where pain may be experienced. For example,pain may occur at a patient's knees 21, hips 22, fingers 23, thumbs 24,neck 25, and spine 26. Thus, the patient may experience pain and/orinflammation in these and other areas.

The statin may be used for localized and/or targeted delivery to apatient to treat pain and/or inflammation associated with differentdiseases or condition such as for example, rheumatoid arthritis,osteoarthritis, spondilothesis, stenosis, sciatica, carpal/tarsal tunnelsyndrome, lower back pain, lower extremity pain, upper extremity pain,cancer, tissue pain, pain associated with injury, surgery or repair ofcervical, thoracic, and/or lumbar vertebrae or intervertebral discs,rotator cuff, articular joint, TMJ, tendons, ligaments, muscles, or thelike.

Pain can be categorized into three groups: (1) acute pain; (2)continuous pain in terminally ill patients; and (3) other forms ofchronic pain. In acute pain, a specific noxious stimulant of limitedduration can be identified. Acute pain is often characterized by adistinct onset, usually with identifiable etiology such as trauma orsurgery. In contrast to acute pain, neuropathic pain serves nobeneficial purpose. Neuropathic pain results when pain associated withan injury or infection continues in an area once the injury or infectionhas resolved. Pain includes nociception and the sensation of pain, bothof which can be assessed objectively and subjectively, using pain scoresand other methods well known in the art.

In various embodiments, pain may include allodynia (e.g., increasedresponse to a normally non-noxious stimulus) or hyperalgesia (e.g.,increased response to a normally noxious or unpleasant stimulus), whichcan in turn be thermal or mechanical (tactile) in nature. In someembodiments, pain is characterized by thermal sensitivity, mechanicalsensitivity and/or resting pain. In other embodiments, pain comprisesmechanically-induced pain or resting pain. In still other embodiments,the pain comprises resting pain. The pain can be primary or secondarypain, as is well known in the art.

Sciatica provides an example of pain that can transition from acute toneuropathic pain. Sciatica refers to pain associated with the sciaticnerve which runs from the lower part of the spinal cord (the lumbarregion), down the back of the leg and to the foot. Sciatica generallybegins with a herniated disc. The herniated disc itself leads to localimmune system activation. The herniated disc also may damage the nerveroot by pinching or compressing it, leading to additional immune systemactivation in the area. In various embodiments, the statin may be usedto reduce, treat, or prevent sciatic pain and/or inflammation by locallyadministering the statin at one or more target tissue sites (e.g., nerveroot, dorsal root ganglion, focal sites of pain, at or near the spinalcolumn, etc.).

The statin may also be used in conjunction with other pain managementmedication. The term “pain management medication” includes one or moretherapeutic agents that are administered to reduce, prevent, alleviateor remove pain entirely. These include anti-inflammatory agents, musclerelaxants, analgesics, anesthetics, narcotics, etc., or combinationsthereof.

In various embodiments, the post-surgical pain or postoperative pain orsurgery-induced pain, is accompanied by inflammation. Inflammation canbe an acute response to trauma or surgery. When tissues are damaged,TNF-α attaches to cells to cause them to release other cytokines thatcause inflammation. The purpose of the inflammatory cascade is topromote healing of the damaged tissue, but once the tissue is healed theinflammatory process does not necessarily end. Left unchecked, this canlead to degradation of surrounding tissues and associated pain. Thus,pain can become a disease state in itself. That is, when this pathway isactivated, inflammation and pain ensue. Often a vicious and seeminglyendless cycle of insult, inflammation, and pain sets in.

One exemplary embodiment where the depot is suitable for use in painand/or inflammation management (e.g., post operative pain and/orinflammation management) is illustrated in FIG. 2. Schematically shownin FIG. 2 is a dorsal view of the spine and sites where the drug depotmay be inserted using a cannula or needle beneath the skin 34 to aspinal site 32 (e.g., spinal disc space, spinal canal, soft tissuesurrounding the spine, nerve root, etc.) and one or more drug depots 28and 32 are delivered to various sites along the spine. In this way, whenseveral drug depots are to be implanted, they are implanted in a mannerthat optimizes location, accurate spacing, and drug distribution, whichcan optimize statin treatment.

Although the spinal site is shown, as described above, the drug depotcan be delivered to any site beneath the skin, including, but notlimited to, at least one muscle, ligament, tendon, cartilage, spinaldisc, spinal foraminal space, near the spinal nerve root, or spinalcanal. In various embodiments, the drug depot containing a statin can beadministered to the patient intra-operatively, intravenously,intramuscularly, SC, intrathecally, intradiskally, peridiskally,epidurally, perispinally, or parenterally or combinations thereof.

The term “patient” refers to organisms from the taxonomy class“mammalian,” including but not limited to humans, other primates such aschimpanzees, apes orangutans and monkeys, rats, mice, cats, dogs, cows,horses, etc.

In various embodiments, a strategy of triangulation may be effectivewhen administering multiple drug depot formulations. Thus, a plurality(at least two, at least three, at least four, at least five, at leastsix, at least seven, etc.) drug depots comprising the pharmaceuticalformulations may be placed around the target tissue site (also known asthe pain generator or pain generation site) such that the target tissuesite falls within a region that is either between the formulations whenthere are two, or within an area whose perimeter is defined by a set ofplurality of formulations.

FIG. 3 shows the effect of a statin (lovastatin) at different doses onpain sensitivity as measured by paw withdrawal latency to thermalradiant heat stimuli, which is a widely used nociceptive measure tostudy the hyperalgesic mechanisms. Lovastatin was administered byintraperitoneal injection at a dose of 3 mg/kg/day or 0.3 mg/kg/day for15 days and sulindac was administered by intraperitoneal injection at adose of 2 mg/kg/day for 15 days. Paw withdrawal was measured whenthermal radiant heat was applied and compared to the control, where theanimals were given PBS vehicle, on days 7 and 14. The data show thatlovastatin at a dose of 3 mg/kg/day or 0.3 mg/kg/day for 15 days andsulindac at a dose of 2 mg/kg/day for 15 days is effective at reducingpain. Sulindac 2 mg/kg/day for 15 days and lovastatin at doses of 3mg/kg/day at day 14 were particularly effective. Lower dose lovastatinat 0.3 mg/kg/day at 7 days and 14 days showed similar reduction in pain.

FIG. 4 shows the effect of a statin (lovastatin) at different doses onpain sensitivity as measured by the von Frey monofilament test(mechanical stimulation) widely used to determine tactile allodynia. Thevon Frey test utilizes monofilament fibers inserted into a holder thatallow a scientist to exert a defined pressure on a punctiform area ofthe paw. The animals are repeatedly mechanically stimulated withincreasingly strong filaments to determine the threshold wherenocifensive paw withdrawal response is reliably elicited. Lovastatin wasadministered by intraperitoneal injection at a dose of 3 mg/kg/day or0.3 mg/kg/day for 15 days and sulindac was administered byintraperitoneal injection at a dose of 2 mg/kg/day for 15 days. Pawwithdrawal was measured when mechanical stimulation was applied andcompared to the control, where the animals were given PBS vehicle, atdays 8 and 15. The data show that lovastatin at a dose of 3 mg/kg/day or0.3 mg/kg/day for 15 days and sulindac at a dose of 2 mg/kg/day for 15days is effective at reducing pain. Sulindac 2 mg/kg/day for 15 days andlovastatin at doses of 3 mg/kg/day at day 15 were particularlyeffective. Lower dose lovastatin at 0.3 mg/kg/day at days 8 and 15showed similar reduction in pain. FIG. 5 shows the effect of a statin(lovastatin) at milligram, microgram, and nanogram doses on painsensitivity as measured by paw withdrawal latency to thermal radiantheat stimuli, which is a widely used nociceptive measure to study thehyperalgesic mechanisms. FIG. 6 shows the effect of a statin(lovastatin) at milligram, microgram, and nanogram doses on painsensitivity as measured by the von Frey filament test widely used todetermine tactile allodynia.

Method of Making Statin Depots

In various embodiments, the drug depot comprising the statin can be madeby combining a biocompatible polymer (as discussed above) and atherapeutically effective amount of a statin or pharmaceuticallyacceptable salt thereof and forming the implantable drug depot from thecombination.

Various techniques are available for forming at least a portion of adrug depot from the biocompatible polymer(s), therapeutic agent(s), andoptional materials, including solution processing techniques and/orthermoplastic processing techniques. Where solution processingtechniques are used, a solvent system is typically selected thatcontains one or more solvent species. The solvent system is generally agood solvent for at least one component of interest, for example,biocompatible polymer and/or therapeutic agent. The particular solventspecies that make up the solvent system can also be selected based onother characteristics, including drying rate and surface tension.

Solution processing techniques include solvent casting techniques, spincoating techniques, web coating techniques, solvent spraying techniques,dipping techniques, techniques involving coating via mechanicalsuspension, including air suspension (e.g., fluidized coating), ink jettechniques and electrostatic techniques. Where appropriate, techniquessuch as those listed above can be repeated or combined to build up thedepot to obtain the desired release rate and desired thickness.

In various embodiments, a solution containing solvent and biocompatiblepolymer are combined an placed in a mold of the desired size and shape.In this way, polymeric regions, including barrier layers, lubriciouslayers, and so forth can be formed. If desired, the solution can furthercomprise, one or more of the following: a statin and other therapeuticagent(s) and other optional additives such as radiographic agent(s),etc. in dissolved or dispersed form. This results in a polymeric matrixregion containing these species after solvent removal. In otherembodiments, a solution containing solvent with dissolved or dispersedtherapeutic agent is applied to a pre-existing polymeric region, whichcan be formed using a variety of techniques including solutionprocessing and thermoplastic processing techniques, whereupon thetherapeutic agent is imbibed into the polymeric region.

Thermoplastic processing techniques for forming the depot or portionsthereof include molding techniques (for example, injection molding,rotational molding, and so forth), extrusion techniques (for example,extrusion, co-extrusion, multi-layer extrusion, and so forth) andcasting.

Thermoplastic processing in accordance with various embodimentscomprises mixing or compounding, in one or more stages, thebiocompatible polymer(s) and one or more of the following: a statin,optional additional therapeutic agent(s), radiographic agent(s), and soforth. The resulting mixture is then shaped into an implantable drugdepot. The mixing and shaping operations may be performed using any ofthe conventional devices known in the art for such purposes.

During thermoplastic processing, there exists the potential for thetherapeutic agent(s) to degrade, for example, due to elevatedtemperatures and/or mechanical shear that are associated with suchprocessing. For example, a statin may undergo substantial degradationunder ordinary thermoplastic processing conditions. Hence, processing ispreferably performed under modified conditions, which prevent thesubstantial degradation of the therapeutic agent(s). Although it isunderstood that some degradation may be unavoidable during thermoplasticprocessing, degradation is generally limited to 10% or less. Among theprocessing conditions that may be controlled during processing to avoidsubstantial degradation of the therapeutic agent(s) are temperature,applied shear rate, applied shear stress, residence time of the mixturecontaining the therapeutic agent, and the technique by which thepolymeric material and the therapeutic agent(s) are mixed.

Mixing or compounding biocompatible polymer with therapeutic agent(s)and any additional additives to form a substantially homogenous mixturethereof may be performed with any device known in the art andconventionally used for mixing polymeric materials with additives.

Where thermoplastic materials are employed, a polymer melt may be formedby heating the biocompatible polymer, which can be mixed with variousadditives (e.g., therapeutic agent(s), inactive ingredients, etc.) toform a mixture. A common way of doing so is to apply mechanical shear toa mixture of the biocompatible polymer(s) and additive(s). Devices inwhich the biocompatible polymer(s) and additive(s) may be mixed in thisfashion include devices such as single screw extruders, twin screwextruders, banbury mixers, high-speed mixers, ross kettles, and soforth.

Any of the biocompatible polymer(s) and various additives may bepremixed prior to a final thermoplastic mixing and shaping process, ifdesired (e.g., to prevent substantial degradation of the therapeuticagent among other reasons).

For example, in various embodiments, a biocompatible polymer isprecompounded with a radiographic agent (e.g., radio-opacifying agent)under conditions of temperature and mechanical shear that would resultin substantial degradation of the therapeutic agent, if it were present.This precompounded material is then mixed with the therapeutic agentunder conditions of lower temperature and mechanical shear, and theresulting mixture is shaped into the statin containing drug depot.Conversely, in another embodiment, the biocompatible polymer can beprecompounded with the therapeutic agent under conditions of reducedtemperature and mechanical shear. This precompounded material is thenmixed with, for example, a radio-opacifying agent, also under conditionsof reduced temperature and mechanical shear, and the resulting mixtureis shaped into the drug depot.

The conditions used to achieve a mixture of the biocompatible polymerand therapeutic agent and other additives will depend on a number offactors including, for example, the specific biocompatible polymer(s)and additive(s) used, as well as the type of mixing device used.

As an example, different biocompatible polymers will typically soften tofacilitate mixing at different temperatures. For instance, where a depotis formed comprising PLGA or PLA polymer, a radio-opacifying agent(e.g., bismuth subcarbonate), and a therapeutic agent prone todegradation by heat and/or mechanical shear (e.g., a statin), in variousembodiments, the PGLA or PLA can be premixed with the radio-opacifyingagent at temperatures of about, for example, 150° C. to 170° C. Thetherapeutic agent is then combined with the premixed composition andsubjected to further thermoplastic processing at conditions oftemperature and mechanical shear that are substantially lower than istypical for PGLA or PLA compositions. For example, where extruders areused, barrel temperature, volumetric output are typically controlled tolimit the shear and therefore to prevent substantial degradation of thetherapeutic agent(s). For instance, the therapeutic agent and premixedcomposition can be mixed/compounded using a twin screw extruder atsubstantially lower temperatures (e.g., 100-105° C.), and usingsubstantially reduced volumetric output (e.g., less than 30% of fullcapacity, which generally corresponds to a volumetric output of lessthan 200 cc/min). It is noted that this processing temperature is wellbelow the melting points of different statins, because processing at orabove these temperatures will result in substantial therapeutic agentdegradation. It is further noted that in certain embodiments, theprocessing temperature will be below the melting point of all bioactivecompounds within the composition, including the therapeutic agent. Aftercompounding, the resulting depot is shaped into the desired form, alsounder conditions of reduced temperature and shear.

In other embodiments, biodegradable polymer(s) and one or moretherapeutic agents are premixed using non-thermoplastic techniques. Forexample, the biocompatible polymer can be dissolved in a solvent systemcontaining one or more solvent species. Any desired agents (for example,a radio-opacifying agent, a therapeutic agent, or both radio-opacifyingagent and therapeutic agent) can also be dissolved or dispersed in thesolvents system. Solvent is then removed from the resultingsolution/dispersion, forming a solid material. The resulting solidmaterial can then be granulated for further thermoplastic processing(for example, extrusion) if desired.

As another example, the therapeutic agent can be dissolved or dispersedin a solvent system, which is then applied to a pre-existing drug depot(the pre-existing drug depot can be formed using a variety of techniquesincluding solution and thermoplastic processing techniques, and it cancomprise a variety of additives including a radio-opacifying agentand/or a viscosity enhancing agent), whereupon the therapeutic agent isimbibed on or in the drug depot. As above, the resulting solid materialcan then be granulated for further processing, if desired.

Typically, an extrusion processes may be used to form the drug depotcomprising a biocompatible polymer(s), therapeutic agent(s) andradio-opacifying agent(s). Co-extrusion may also be employed, which is ashaping process that can be used to produce a drug depot comprising thesame or different layers or regions (for example, a structure comprisingone or more polymeric matrix layers or regions that have permeability tofluids to allow immediate and/or sustained drug release). Multi-regiondepots can also be formed by other processing and shaping techniquessuch as co-injection or sequential injection molding technology.

In various embodiments, the depot that may emerge from the thermoplasticprocessing (e.g., ribbon, pellet, strip, etc.) is cooled. Examples ofcooling processes include air cooling and/or immersion in a coolingbath. In some embodiments, a water bath is used to cool the extrudeddepot. However, where a water-soluble therapeutic agent such aslovastatin is used, the immersion time should be held to a minimum toavoid unnecessary loss of therapeutic agent into the bath.

In various embodiments, immediate removal of water or moisture by use ofambient or warm air jets after exiting the bath will also preventre-crystallization of the drug on the depot surface, thus controlling orminimizing a high drug dose “initial burst” or “bolus dose” uponimplantation or insertion if this release profile is not desired.

In various embodiments, the drug depot can be prepared by mixing orspraying the drug with the polymer and then molding the depot to thedesired shape. In various embodiments, lovastatin is used and mixed orsprayed with the PLGA or PEG550 polymer, and the resulting depot may beformed by extrusion and dried.

Having now generally described the invention, the same may be morereadily understood through the following reference to the followingexamples, which are provided by way of illustration and are not intendedto limit the present invention unless specified.

EXAMPLES

The behavioral animal model of chronic constriction injury (“CCI”) waschosen to evaluate the efficacy of lovastatin as a pain treatment. Thismodel may mimic pain associated with sciatica in humans.

Example 1

Surgical Procedures Twenty-eight male Wister rats (Charles RiverLaboratories, Wilmington, Mass.) weighing 300±26 g the day of surgery(Day 1) were used in this study. All experiments were conducted inaccordance with the International Association for the Study of Painguidelines and approved by the Institutional Animal Care and UseCommittee at SRI International, Inc (Menlo Park, Calif.). CCI wasinduced according to the method of Bennett and Xie. Briefly, each animalwas anesthetized by intraperitoneal (IP) injection of sodiumpentobarbital at a dose of 60 mg/kg. The animal's common sciatic nervewas exposed and freed from adherent tissue at mid-thigh by separatingthe biceps femoris muscles by blunt dissection. Four loose ligatureswere placed 1 mm apart, using chromic gut suture (4-0 absorbable suture;Jorgensen Laboratories, Inc., Loveland, Colo.).

Treatment Groups

Seven animals were randomly assigned to each treatment group. Animalswere dosed for 15 days as indicated in Table 1.

TABLE 1 Dosing Concentration Group of inject, Number Treatment Dosemg/mL Comments 1 Vehicle 1 cc NA Vehicle (PBS [pH 8.0]) 2 Sulindac 2mg/kg 0.70 Positive control; IP daily 3 Lovastatin 3 mg/kg 1.05 IP daily4 Lovastatin 0.3 mg/kg 0.105 IP Daily

Example 2

Assessment of Behavior

Withdrawal latencies to a noxious thermal stimulus were measuredaccording to the Hargreaves test using a plantar analgesia instrument(Stoelting, Wood Dale, Ill.) on Days −2 (baseline), 7, and 14. Theradiant infrared heat source stimulus intensity was set to IR50 and thecut-off time was set at 15 seconds. Rats were placed on a glass platformand allowed to habituate to the testing chambers for a minimum of 15minutes prior to each testing session. The thermal stimulus was appliedto the plantar surface of the paw. Thermal thresholds were defined asthe latency in seconds at the first pain behavior, which includes pawwithdrawal, flinching, biting and/or licking of the stimulated paw. Thereadings for all animals were averaged and the mean and standard errorof the mean (SEM) were determined for each treatment group.

The results are graphically shown in FIG. 3. This figure show the effectof a statin (lovastatin) at different doses on pain sensitivity asmeasured by paw withdrawal latency to thermal radiant heat stimuli,which is a widely used nociceptive measure to study the hyperalgesicmechanisms. Paw withdrawal was measured when thermal radiant heat wasapplied and compared to the control, where the animals were given PBSvehicle. The data show that lovastatin at a dose of 3 mg/kg/day or 0.3mg/kg/day for 15 days and sulindac at a dose of 2 mg/kg/day for 154 daysis effective at reducing pain. Sulindac 2 mg/kg/day at 7 and 14 days andlovastatin at a dose of 3 mg/kg/day at 14 days were particularlyeffective at reducing pain. Lower dose lovastatin at 0.3 mg/kg/day at 7and 14 days showed similar reduction in pain.

Mechanical allodynia was measured using von Frey monofilaments(Stoelting, Wood Dale, Ill.) with varying stiffness (2.0-15.0 g) on Days−1 (baseline), 8, and 15 as described previously. Animals were placed ona perforated metallic platform and allowed to habituate to theirsurroundings for a minimum of 15 minutes before testing. The 50% pawwithdrawal threshold response was determined by a sequential increasingand/or decreasing of the stimulus strength (the “up-down method” ofDixon). Each filament was applied with enough pressure to cause abuckling effect. Absence of a paw lifting/withdrawal response after 5seconds prompted the use of the filament of next higher weight. Pawwithdrawal indicating a positive response prompted the use of a weakerfilament. After the initial response (i.e., paw withdrawal), the testingcontinued for four additional measurements and was used to calculate theresponse threshold. Four consecutive positive responses received a scoreof 0.25 g, and five consecutive negative responses (i.e., no pawwithdrawal) received a score of 15 g. The 50% paw withdrawal thresholdwas calculated using the formula: 10 (Xf+kd)/10,000, where Xf is thefinal von Frey filament used (log units), k is a value that analyzes theresponse pattern (taken from the table published by Chaplan et al.), andd is the mean difference between stimuli (log units). The mean andstandard error of the mean (SEM) were determined for each treatmentgroup.

The results are graphically shown in FIG. 4. This figure shows theeffect of a statin (lovastatin) at different doses on pain sensitivityas measured by the von Frey filament test (mechanical stimulation)widely used to determine tactile allodynia. The data show thatlovastatin at a dose of 3 mg/kg/day or 0.3 mg/kg/day for 15 days andsulindac at a dose of 2 mg/kg/day for 15 days is effective at reducingpain. Sulindac 2 mg/kg/day at 8 and 15 days and lovastatin at doses of 3mg/kg/day at 15 days were particularly effective. Lower dose lovastatinat 0.3 mg/kg/day at and 15 days showed similar reduction in pain.

Example 3

Thermal hyperalgesia was performed using, among other things, 50:50DMSO/PBS as the vehicle control, which consistently records a withdrawaltime that is about 42% of per-operative baseline. The 0.3 mg/kg/day IPdose reduced this pain behavioral response at all days tested. Afterreducing this behavioral response to 68% on Day 7, this group heldconsistently at 61% for days 14 and 21. The high dose lovastatin pumpgroup (0.4 mcg/hr; 10-fold reduction from 0.3 mg/kg/day) steadilyimproved during the course of the study, and by day 21 recorded a scorethat should be statistically equivalent to the other two statin groups.The low dose for the lovastatin group (100-fold decrease from the 0.3mg/kg/day group) recorded showed consistent withdrawal scores near 60%of baseline on all testing days. These scores should be statisticallyequivalent to the 0.3 mg/kg/day group. This may indicate the upper-doselimit for this localized depot application. FIG. 5 graphicallyillustrates the effect of lovastatin at milligram, microgram, andnanogram doses on pain sensitivity as measured by paw withdrawal latencyto thermal radiant heat stimuli.

Example 4

Mechanical allodynia: This behavioral assessment is always interestingin this model. Particularly interesting is the decrease in mechanicalthresholds on day 15. 50:50 DMSO/PBS showed a severe reduction inmechanical allodynia over the course of this experiment. Lovastatindosed at 0.4 mcg/hr is probably statistically equivalent to the vehiclecontrol in reducing this pain response. Lovastatin at 0.3 mg/kg/day wasable to reduce this pain behavioral response at all time points, and the40 ng/hr group is probably statistically equivalent. FIG. 6 graphicallyillustrates the results of this experiment where the effect oflovastatin at milligram, microgram, and nanogram doses on painsensitivity was measured using this model.

These experiments show that lovastatin is effective at reducing painand/or inflammation.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to various embodimentsdescribed herein without departing from the spirit or scope of theteachings herein. Thus, it is intended that various embodiments coverother modifications and variations of various embodiments within thescope of the present teachings.

1. A method of treating or preventing pain and/or inflammation fromsciatica, stenosis or spondilothesis in a patient in need of suchtreatment, the method comprising locally administering a therapeuticallyeffective amount of a statin or pharmaceutically acceptable salt thereofat or near a target tissue site beneath the skin of the patient to treator prevent sciatic pain and/or inflammation.
 2. A method of treating orpreventing pain and/or inflammation according to claim 1, wherein thestatin is administered by local injection or infusion.
 3. A method oftreating or preventing pain and/or inflammation according to claim 1,wherein the method comprises locally administering one or more drugdepots comprising the therapeutically effective amount of the statin orpharmaceutically acceptable salt thereof, the drug depot capable ofreleasing an effective amount of a statin or pharmaceutically acceptablesalt thereof at or near the target tissue site.
 4. A method of treatingor preventing pain and/or inflammation according to claim 3, wherein thedrug depot is biodegradable and releases an effective amount of a statinor pharmaceutically acceptable salt thereof over a period of at leastone day to 6 months.
 5. A method of treating or preventing pain and/orinflammation according to claim 1, wherein the target tissue sitecomprises at least one muscle, ligament, tendon, cartilage, spinal disc,spinal foraminal space near the spinal nerve root, facet or synovialjoint, or spinal canal.
 6. A method of treating or preventing painand/or inflammation according to claim 3, wherein the drug depot isadministered at one more target tissue sites at or near the sciaticnerve.
 7. A method of treating or preventing pain and/or inflammationaccording to claim 1, wherein the statin comprises at leastcerivastatin, atorvastatin, simvastatin, pravastatin, fluvastatin,lovastatin, rosuvastatin, eptastatin, pitavastatin, velostatin,fluindostatin, dalvastain, or pharmaceutically acceptable salts thereofor a combination thereof.
 8. A method of treating or preventing painand/or inflammation according to claim 1, wherein the statin compriseslovastatin and is administered at a dose of about 0.3 mg/kg/day to about3 mg/kg/day.
 9. A method of treating or preventing pain and/orinflammation according to claim 3, wherein the drug depot releases 5%,10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% ofthe statin or pharmaceutically acceptable salt thereof relative to atotal amount of statin loaded in the drug depot over a period of one dayto 6 months after the drug depot is administered to the target tissuesite.
 10. A method of treating or preventing pain and/or inflammationaccording to claim 3, wherein the drug depot releases 40 ng to about 5mg of the statin or pharmaceutically acceptable salt thereof every hourto treat or prevent sciatic pain and/or inflammation.
 11. A method oftreating or preventing pain and/or inflammation according to claim 3,wherein the drug depot comprises at least one anti-inflammatory oranalgesic agent, at least one anabolic or an anti-catabolic growthfactor or a combination thereof.
 12. A method of treating or preventingpain and/or inflammation according to claim 3, wherein the statin orpharmaceutically acceptable salt thereof is encapsulated in a pluralityof depots comprising microparticles, microspheres, microcapsules, and/ormicrofibers suspended in a gel.
 13. A method of reducing pain and/orinflammation from sciatica, stenosis or spondilothesis in a patient inneed of such treatment, the method comprising locally administering atherapeutically effective amount of a statin or pharmaceuticallyacceptable salt thereof at or near a target tissue site beneath the skinof the patient.
 14. A method of reducing pain and/or inflammationaccording to claim 13, wherein the statin is administered by localinjection or infusion.
 15. A method of treating or preventing painand/or inflammation according to claim 13, wherein the method compriseslocally administering one or more drug depots comprising thetherapeutically effective amount of the statin or pharmaceuticallyacceptable salt thereof, the drug depot capable of releasing aneffective amount of a statin or pharmaceutically acceptable salt thereofat or near the target tissue site.
 16. A method of reducing pain and/orinflammation according to claim 15, wherein one or more drug depotsrelease an effective amount of a statin or pharmaceutically acceptablesalt thereof over a period of one day to 6 months.
 17. A method ofreducing pain and/or inflammation according to claim 13, wherein thestatin comprises at least cerivastatin, atorvastatin, simvastatin,pravastatin, fluvastatin, lovastatin, rosuvastatin, pitavastatin,velostatin, fluindostatin, dalvastain, or pharmaceutically acceptablesalts thereof or a combination thereof.
 18. An implantable drug depotuseful for reducing, preventing or treating pain and/or inflammation ina patient in need of such treatment, the implantable drug depotcomprising a therapeutically effective amount of a statin orpharmaceutically acceptable salt thereof, the depot being implantable ata site beneath the skin to reduce, prevent or treat pain and/orinflammation, wherein the drug depot is capable of releasing aneffective amount of a statin or pharmaceutically acceptable salt thereofover a period of at least one day.
 19. An implantable drug depotaccording to claim 18, wherein the drug depot is biodegradable andcomprises (i) one or more immediate release layer(s) that releases abolus dose of the statin or pharmaceutically acceptable salt thereof ata site beneath the skin and (ii) one or more sustain release layer(s)that releases an effective amount of the statin or pharmaceuticallyacceptable salt thereof over a period of one day to 6 months.
 20. Animplantable drug depot according to claim 18, wherein the one or moreimmediate release layer(s) comprise poly (lactide-co-glycolide) (PLGA)and the one or more sustain release layer(s) comprise polylactide (PLA).